Compounds and compositions for inducing chondrogenesis

ABSTRACT

The present invention provides compounds of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds, and methods of using such compounds for treatment of joint damage or joint injury in a mammal, and for inducing differentiation of mesenchymal stem cells into chondrocytes.

CROSS-REFERENCED TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/848,568 filed 14 Apr. 2020; which is a continuation of U.S. patentapplication Ser. No. 16/448,547 filed 21 Jun. 2019, now U.S. Pat. No.10,660,881; which is a continuation of U.S. patent application Ser. No.16/203,122 filed 28 Nov. 2018, now U.S. Pat. No. 10,383,863; which is adivisional of U.S. patent application Ser. No. 15/587,652 filed 5 May2017, now U.S. Pat. No. 10,188,638; which is a divisional of U.S. patentapplication Ser. No. 14/709,852 filed 12 May 2015, now U.S. Pat. No.9,688,689; which claims the benefit of priority to U.S. ProvisionalPatent Application No. 61/992,815 filed 13 May 2014. Each of theseapplications is incorporated herein by reference in its entirety and forall purposes.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to the identification of a class ofcompounds, pharmaceutical compositions comprising such compounds andmethods of using such compounds to treat joint damage resulting fromjoint injury and arthritis in a mammal.

Background

Osteoarthritis (OA) represents the most common musculoskeletal disorder.Approximately 40 million Americans are currently affected and thisnumber is predicted to increase to 60 million within the next twentyyears as a result of the aging population and an increase in lifeexpectancy, making it the fourth leading cause of disability. OA ischaracterized by a slow degenerative breakdown of the joint includingboth the articular cartilage (containing the cells and matrix whichproduce lubrication and cushioning for the joint) and the subchondralbone underlying the articular cartilage. OA can be considered aconsequence of various etiologic factors. For example, it can be causedby abnormal biomechanical stress or genetic or acquired abnormalities ofarticular cartilage or bone. Current OA therapies include pain reliefwith oral NSAIDs or selective cyclooxygenase 2 (COX-2) inhibitors,intra-articular (IA) injection with agents such as corticorsteroids andhyaluronan, and surgical approaches.

Joint damage, e.g., acute joint injury, such as a meniscal or ligamenttear, or an intra-articular fracture can also lead to arthritis, e.g.,posttraumatic arthritis. Because articular cartilage has a limitedability to repair, even small undetectable damage can often get worseover time and lead to OA. Current treatments for joint injury caninclude surgery and other invasive procedures focused on regeneration ofdamaged joints as well as treatment with agents to reduce pain andinflammation.

Mesenchymal stem cells (MSCs) are present in adult articular cartilageand upon isolation can be programmed in vitro to undergo differentiationto chondrocytes and other mesenchymal cell lineages, and may be used forcartilage regeneration. In part, the process is regulated by growthfactors (TGFβs, BMPs), serum conditions and cell-cell contact.WO2011/008773 describes peptide compositions and use of thosecompositions for treating or preventing arthritis and joint injury andfor inducing differentiation of mesenchymal cells into chondrocytes.Additionally, WO2012/129562 describes small molecule compounds,compositions and use of those compositions for amelioration of arthritisand joint injury and for inducing differentiation of mesenchymal cellsinto chondrocytes.

Though surgical techniques, and regenerative technology have made someprogress in restoration of cartilage, slowing degeneration, and improvedrepair of joint damage, a continued need exists for improvement ofcompositions and methods for effective cartilage regeneration, treatmentof joint damage and amelioration or prevention of OA.

BRIEF SUMMARY OF THE INVENTION

The invention therefore relates to a compound of the formula (I):

or a pharmaceutically acceptable salt, or stereoisomer thereof; wherein

-   -   “-----” represents a single or double bond;    -   A is CR^(8a)R^(8b), NR⁹, or O; wherein R^(8a), R^(8b) and R⁹ are        each independently hydrogen or C₁₋₆alkyl;    -   L is *—C(O)NR¹⁰— or *—C(O)O—, wherein “*” represents the point        of attachment of L to the bicyclic ring containing A, and R¹⁰ is        hydrogen or C₁₋₆alkyl;    -   R⁰ is selected from hydrogen and C₁₋₆alkyl;    -   R¹ is selected from halo, cyano, —C(O)R¹¹, —C(O)NR^(12a)R^(12b),        —C(O)ONR^(12a)R^(12b), 5- and 6-membered heterocycloalkyl, 5-        and 6-membered heterocyclyl, phenyl, and 5- to 9-membered        heteroaryl, wherein        -   R¹¹ is hydrogen or C₁₋₆alkyl;        -   R^(12a) and R^(12b) are each independently hydrogen or            C₁₋₆alkyl;        -   the heterocycloalkyl, heterocyclyl, phenyl, or heteroaryl of            R¹ is unsubstituted or substituted by 1 to 2 substituents            independently selected from halo, cyano, C₁₋₆alkyl,            C₁₋₆haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b), 5- and            6-membered heterocycloalkyl, phenyl, and 5- and 6-membered            heteroaryl; wherein            -   R¹³ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,                amino, and C₁₋₆alkylamino;            -   R^(14a) and R^(14b) are each independently selected from                hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, —C(O)OR¹⁵, and —S(O)₂R¹⁵,                wherein R¹⁵ is hydrogen or C₁₋₆alkyl; and            -   the heterocycloalkyl, phenyl or heteroaryl substituent                of R¹ is further substituted by 1 to 2 substituents                independently selected from halo, C₁₋₆alkyl,                C₁₋₆haloalkyl, and hydroxy;    -   R³ is selected from C₁₋₆alkyl, C₁₋₆haloalkyl, 3- to 6-membered        cycloalkyl, (159), 4- to 7-membered heterocycloalkyl, 5- to        10-membered heterocyclyl, phenyl, and 5- to 9-membered        heteroaryl, wherein        -   the cycloalkyl, heterocycloalkyl, heterocyclyl, phenyl, or            heteroaryl of R³ is unsubstituted or substituted by 1 to 2            substituents independently selected from halo, cyano,            C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,            —C(O)R¹⁶, —C(O)OR¹⁶, —S(O)₂R¹⁶, 5 and 6 membered            heterocycloalkyl, and phenyl; wherein            -   R¹⁶ is hydrogen or C₁₋₆alkyl;            -   the phenyl or heterocycloalkyl substituent or R³ is                unsubstituted or further substituted by 1 to 2                substituents independently selected from halo, cyano,                C₁₋₆alkyl, and C₁₋₆haloalkyl; and    -   R² and R⁴ are each hydrogen or C₁₋₆alkyl; or R² and R⁴ taken        together form a cyclopropyl ring fused to the bicyclic ring        containing A; or R² and R⁴ taken together form a bond producing        a double bond between the two carbons to which R² and R⁴ are        attached; and    -   R⁵ is hydrogen or C₁₋₆alkyl, or R⁵ and R¹⁰ taken with the atoms        to which they are linked form a 5- or 6-membered ring fused to        the bicyclic ring containing A; and    -   R⁶ and R⁷ are each hydrogen or C₁₋₆alkyl; or R⁶ and R⁷ taken        together form a bond producing a double bond between the two        carbons to which R⁶ and R⁷ are attached.

In a second aspect, the present invention provides a pharmaceuticalcomposition containing a compound of Formula I, or a sub-formulathereof, where the compound is present in a single stereoisomer or amixture of stereoisomers thereof; or a pharmaceutically acceptable saltthereof, in admixture with one or more suitable excipients.

In a third aspect, the present invention relates to a pharmaceuticalcomposition formulated for intra-articular delivery, the compositionincluding a pharmaceutically effective amount of a compound of FormulaI, or a a sub-formula thereof, where the compound is present as a singlestereoisomer or a mixture of stereoisomers thereof; or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In a fourth aspect, the present invention provides methods of treating asubject comprising administering a therapeutically effectively amount ofa compound of Formula I, or a sub-formula thereof, a pharmaceutical saltthereof, or a pharmaceutical composition thereof. Provided methodsinclude treating a subject having or at risk of having joint damageand/or arthritis, comprising administering to the subject atherapeutically effective amount of one or more compounds of theinvention or a pharmaceutical composition thereof.

In a fifth aspect, the present invention further provides a method fortreating, ameliorating or preventing arthritis or joint damage in amammal in need thereof, where the method comprises administering to ajoint of a patient a therapeutically effective amount of a compound offormula I, or a sub-formula thereof, a pharmaceutical salt thereof, or apharmaceutical composition thereof. Examples of conditions that canbenefit from such methods include, but are not limited to arthritis(e.g., osteoarthritis, traumatic arthritis), and joint damage (e.g.,acute joint injury).

In a sixth aspect, the present invention relates to a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodincluding contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula I or a sub-formula thereof, a pharmaceutical saltthereof, or a pharmaceutical composition thereof.

In a seven aspect, the present invention relates to a method ofincreasing production of collagen in fibroblast, the method includingcontacting fibroblast with a sufficient amount of a compound of FormulaI or a sub-formula thereof, a pharmaceutical salt thereof, or apharmaceutical composition thereof.

In a eighth aspect, the present invention relates to the use of acompound Formula I or a sub-formula thereof, a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition thereof, in themanufacture of a medicament for treating joint injury.

In a ninth aspect, the present invention provides a process forpreparing compounds of Formula I, or a sub-formula thereof, salts andprodrug derivatives, thereof, or pharmaceutical composition thereof.

Unless specified otherwise, the term “compounds of the presentinvention” refers to compounds of Formula (I) and subformulae thereof,salts of the compound, hydrates or solvates of the compounds, salts, aswell as all stereoisomers (including diastereoisomers and enantiomers),tautomers and isotopically labeled compounds (including deuteriumsubstitutions). Compounds of the present invention further comprisepolymorphs of compounds of formula I (or subformulae thereof) and saltsthereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, at least in part, on the identificationof a novel class of compounds that stimulate chondrocyte differentiationof mesenchymal stem cells. WO2012/129562, describes compounds andcompositions and the use of same for treating or preventing arthritisand joint injury and for inducing differentiation of mesenchymal cellsinto chondrocytes. Accordingly, the present invention provides adifferent class of compounds and compositions for repairing cartilage.Also provided are compositions and methods to treat, prevent orameliorate arthritis or joint injury by administering a compound orcomposition of the invention into a joint, a cartilage tissue or acartilage proximal tissue, or systemically. Further, the inventionprovides compositions and methods for induction of mesenchymal stem celldifferentiation into chondrocytes.

Definitions

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

“Alkoxy” as used herein refers the radical —O-alkyl, wherein the alkylis as defined herein. C_(X)alkoxy and C_(X-Y)alkoxy as used hereindescribe alkoxy groups where X and Y indicate the number of carbon atomsin the alkyl chain. Representative examples of C₁₋₁₀alkoxy include, butare not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and decyloxy. Thealkyl portion of the alkoxy may be optionally substituted, and thesubstituents include those described for the alkyl group below.

“Alkyl” as used herein refers to a fully saturated branched orunbranched hydrocarbon chain having up to 10 carbon atoms. C_(X) alkyland C_(X-Y) alkyl as used herein describe alkyl groups where X and Yindicate the number of carbon atoms in the alkyl chain. For example,C₁₋₁₀ alkyl refers to an alkyl radical as defined above containing oneto ten carbon atoms. C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. Alkyl representedalong with another radical like arylalkyl, heteroarylalkyl, alkoxyalkyl,alkoxyalkyl, alkylamino, where the alkyl portion shall have the samemeaning as described for alkyl and is bonded to the other radical. Forexample, (C₆₋₁₀)aryl(C₁₋₃)alkyl includes, benzyl, phenylethyl,1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl andthe like.

Unless stated otherwise specifically in the specification, an alkylgroup may be unsubstituted or substituted by one or more substituents tothe extent that such substitution makes sense chemically. Typicalsubstituents include, but are not limited to halo, hydroxyl, alkoxy,cyano, amino, acyl, aryl, arylalkyl, and cycloalkyl, or an heteroformsof one of these groups, and each of which can be substituted by thesubstituents that are appropriate for the particular group.

“Amino” as used herein refers to the radical —NH₂. When an amino isdescribed as “substituted” or “optionally substituted”, the termincludes NR′R″ wherein each R′ and R″ is independently H, or is analkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyl, arylalkylcycloalkylalkyl group or a heteroform of one of these groups, and eachof the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl or groups orheteroforms of one of these groups, each of which is optionallysubstituted with the substituents described herein as suitable for thecorresponding group.

Unless indicated otherwise, the compounds of the invention containingamino moieties may include protected derivatives thereof. Suitableprotecting groups for amino moieties include acetyl,tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

“Alkylamino” as used herein refers to the radical —NR_(a)R_(b), where atleast one of, or both, R_(a) and R_(b) are an alkyl group as describedherein. An C₁₋₄alkylamino group includes —NHC₁₋₄alkyl and—N(C₁₋₄alkyl)₂; e.g., —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃), —N(CH₂CH₃)₂, andthe like.

“Aromatic” as used herein refers to a moiety wherein the constituentatoms make up an unsaturated ring system, where all atoms in the ringsystem are sp² hybridized and the total number of pi electrons is equalto 4n+2. An aromatic ring may be such that the ring atoms are onlycarbon atoms or may include carbon and non-carbon atoms (seeHeteroaryl).

“Aryl” as used herein refers to a monocyclic or polycyclic aromatic ringassembly containing 6-14 ring atoms where all the ring atoms are carbonatoms. Typically, the aryl is a 6-membered (ring atoms) monocyclic, a10- to 12-membered bicyclic or a 14-membered fused tricyclic aromaticring system. Six to fourteen membered aryls include, but are not limitedto, phenyl, biphenyl, naphthyl, azulenyl, and anthracenyl.

An aryl may be unsubstituted or substituted by 1-5 (such as one, or two,or three) substituents independently selected from the group consistingof hydroxy, thiol, cyano, nitro, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkynyl,C₁₋₄alkoxy, thioC₁₋₄alkyl, C₁₋₄alkenyloxy, C₁₋₄alkynyloxy, halogen,C₁₋₄alkylcarbonyl, carboxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,di-C₁₋₄alkylamino, C₁₋₄alkylaminocarbonyl, di-C₁₋₄alkylaminocarbonyl,C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl,sulfamoyl, alkylsulfamoyl, C₁₋₄alkylaminosulfonyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl, wherein each of the afore-mentionedsubstitutents may be further substituted by one or more substituentsindependently selected from halogen, alkyl, hydroxyl or C₁₋₄alkoxygroups.

When an “aryl” is represented along with another radical like“arylalkyl”, “aryloxyalkyl”, “aryloxycarbonyl”, “aryloxy-carbonylalkyl”,the aryl portion shall have the same meaning as described in theabove-mentioned definition of “aryl”.

“Aryloxy” as used herein, refers to the radical —O-aryl, wherein aryl isas defined herein.

“Bicyclic” or “bicyclyl” as used here in refers to a ring assembly oftwo rings where the two rings are fused together, linked by a singlebond or linked by two bridging atoms. The rings may be a carbocyclyl, aheterocyclyl, or a mixture thereof.

“Bridging ring” as used herein refers to a polycyclic ring system wheretwo ring atoms that are common to two rings are not directly bound toeach other. One or more rings of the ring system may also compriseheteroatoms as ring atoms. Non-exclusive examples of bridging ringsinclude norbornanyl, oxabicyclo[2.2.1]heptanyl,azabicyclo[2.2.1]heptanyl, adamantanyl, and the like.

“Cycloalkyl”, as used herein, means a radical comprising a non-aromatic,saturated monocyclic, bicyclic, tricyclic, fused, bridged or spiropolycyclic hydrocarbon ring system of 3- to 14-ring members where allthe ring members are carbon atoms. Exemplary monocyclic cycloalkylinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, and the like. Exemplarybicyclic cycloalkyls include bicyclo[2.2.1]heptane,bicyclo[3.2.1]octanyl, bornyl, norbornanyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl. Exemplary tricyclic cycloalkyl groups include, forexample, adamantanyl.

A cycloalkyl may be unsubstituted or substituted by one, or two, orthree, or more substituents independently selected from the groupconsisting of hydroxyl, thiol, cyano, nitro, oxo, alkylimino, C₁₋₄alkyl,C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄thioalkyl, C₁₋₄alkenyloxy,C₁₋₄alkynyloxy, halogen, C₁₋₄alkylcarbonyl, carboxy, C₁₋₄alkoxycarbonyl,amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino, C₁₋₄alkylaminocarbonyl,di-C₁₋₄alkylaminocarbonyl, C₁₋₄alkylcarbonylamino,C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl,C₁₋₄alkylaminosulfonyl where each of the afore-mentioned hydrocarbongroups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be furthersubstituted by one or more residues independently selected at eachoccurrence from halogen, hydroxyl or C₁₋₄alkoxy groups.

“Cyano”, as used herein, refers to the radical —CN.

“EC₅₀”, refers to the molar concentration of an inhibitor or modulatorthat produces 50% efficacy.

“IC₅₀”, refers to the molar concentration of an inhibitor or modulatorthat produces 50% inhibition.

“Fused ring”, as used herein, refers to a multi-ring assembly whereinthe rings comprising the ring assembly are so linked that the ring atomsthat are common to two rings are directly bound to each other. The fusedring assemblies may be saturated, partially saturated, aromatics,carbocyclics, heterocyclics, and the like. Non-exclusive examples ofcommon fused rings include decalin, naphthalene, anthracene,phenanthrene, indole, benzofuran, purine, quinoline, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo.

“Haloalkyl”, or halo-substituted-alkyl” as used herein, refers to analkyl as defined herein, which is substituted by one or more halo atomsdefined herein. The haloalkyl can be monohaloalkyl, dihaloalkyl orpolyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo,bromo, chloro or fluoro within the alkyl group. Dihaloalkyl andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups within the alkyl. C_(X)haloalkyland C_(X-Y)haloalkyl are typically used where X and Y indicate thenumber of carbon atoms in the alkyl chain. Non-limiting examples ofC₁₋₄haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. AC₁₋₄perhaloalkyl group refers to a C₁₋₄alkyl group having all hydrogenatoms replaced with halo atoms.

“Heteroaryl”, as used herein, refers to a 5-14 membered aromatic ringassembly (e.g., a 5-7 membered monocycle, an 8-10 membered bicycle, or a13-14 membered tricyclic ring system) having 1 to 8 heteroatoms selectedfrom N, O and S as ring atoms and the remaining ring atoms are carbonatoms. The nitrogen atoms of such heteroaryl rings can be optionallyquaternerized and the sulfur atoms of such heteroaryl rings can beoptionally oxidized. Typical 5- to 7-membered heteroaryl groups includethienyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolinyl,thiazolyl, 1,3,4-thiadiazolyl, isothiazolyl, oxazolyl, oxadiazoleisoxazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl,pyrazinyl, pyrimidinyl, and the like. Bicyclic or tricyclic 8- to14-membered heteroaryls include, but are not limited to, those derivedfrom benzo[b]furan, benzo[b]thiophene, benzimidazole,imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine,thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, quinazolinyle, pteridinyl,indolizine, imidazo[1,2a]pyridine, quinoline, quinolinyl, isoquinoline,phthalazine, quinoxaline, naphthyridine, naphthyridinyl, quinolizine,indole, isoindole, indazole, benzoxazole, benzopyrazole, benzothiazole,imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,purinyl, carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone.

A heteroaryl may be unsubstituted or substituted with one or moresubstituents independently selected from hydroxyl, thiol, cyano, nitro,C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy, thioC₁₋₄alkyl,C₁₋₄alkenyloxy, C₁₋₄alkynyloxy, halogen, C₁₋₄alkylcarbonyl, carboxy,C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino,C₁₋₄alkylaminocarbonyl, di-C₁₋₄alkylaminocarbonyl,C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl,sulfamoyl, alkylsulfamoyl, C₁₋₄alkylaminosulfonyl where each of theafore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl,alkoxy residues) may be further substituted by one or more residuesindependently selected at each occurrence from halogen, hydroxyl orC₁₋₄alkoxy groups.

When a heteroaryl is represented along with another radical like“heteroaryloxy”, “heteroaryloxyalkyl”, “heteroaryloxycarbonyl”, theheteroaryl portion shall have the same meaning as described in theabove-mentioned definition of “heteroaryl”.

“Heteroatom”, as used herein, refers to an atom that is not a carbonatom. Particular examples of heteroatoms include, but are not limited tonitrogen, oxygen, and sulfur.

“Heterocycloalkyl”, as used herein, refers to a 4-15 membered, saturatedmonocyclic or polycyclic ring system, comprising 1-8 heteroatoms as ringatoms and that the remaining ring atoms are carbon atoms. Theheteroatoms are selected from N, O, and S, preferably O and N. Thenitrogen atoms of the heterocycloalkyl can be optionally quaternerizedand the sulfur atoms of the heterocycloalkyl can be optionally oxidized.The heterocycloalkyl can include fused or bridged rings as well asspirocyclic rings. Typically, the heterocycloalkyl is 4- to 8-memberedmonocyclic ring containing 1 to 3 heteroatoms, a 7- to 12-memberedbicyclic ring system containing 1-5 heteroatoms, or a 10- to 15-memberedtricyclic ring system containing 1 to 7 heteroatoms. Examples of 4- to6-membered heterocycloalkyl include those derived from azetidine,tetrahydrofuran (THF), 1, 4-dioxane, morpholine, 1,4-dithiane,piperazine, piperidine, 1,3-dioxolane, imidazolidine, pyrazolidinyl,pyrrolidine, tetrahydropyran, oxathiolane, dithiolane, 1,3-dioxane,1,3-dithiane, oxathiane, thiomorpholine. Examples of bicyclicheterocycloalkyl include, but not limited to, oxabicyclo[2.2.1]heptane,azabicyclo[2.2.1]heptane, and the like.

A heterocycloalkyl may be unsubstituted or substituted with 1-5substituents (such as one, or two, or three) each independently selectedfrom hydroxyl, thiol, cyano, nitro, oxo, alkylimino, C₁₋₄alkyl,C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy, C₁-4thioalkyl, C₁₋₄alkenyloxy,C₁₋₄alkynyloxy, halogen, C₁₋₄alkylcarbonyl, carboxy, C₁₋₄alkoxycarbonyl,amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino, C₁₋₄alkylaminocarbonyl,di-C₁₋₄alkylaminocarbonyl, C₁₋₄alkylcarbonylamino,C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl,C₁₋₄alkylaminosulfonyl where each of the afore-mentioned hydrocarbongroups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be furthersubstituted by one or more residues independently selected at eachoccurrence from halogen, hydroxyl or C₁₋₄alkoxy groups.

When a heterocycloalkyl forms part of other groups like“heterocycloalkyl-alkyl”, “heterocycloalkoxy”, “heterocycloalkyl-aryl”,the heteroaryl portion shall have the same meaning as described in theabove-mentioned definition of “heteroaryl”

“Heterocyclyl” or “heterocycle” as used herein, refers to a partiallysaturated or partially unsaturated 3-14 membered, monocyclic orpolycyclic ring system containing at least one heteroatom moietyselected from the group consisting of N, O, SO, SO₂, (C═O), and S, andpreferably N, O, S, optionally containing one to four additionalheteroatoms in each ring. Heterocyclyl as defined herein also includespolycyclic ring systems that contain a fully saturated ring fused to afully unsaturated ring. Examples of monocyclic heterocyclyl includethose derived from pyrroline, imidazoline, 1,2,3,6-tetrahydropyridine,2H-pyran, 4H-pyran, 3,6-dihydro-2H-pyran, and the like. Examples ofpolycyclic heterocyclyl include those derived from indoline, 3H-indole,carbazole, indene, dihydrobenzo[b][1,4]dioxine fluorene, phenoxazine,and the like.

Hydroxy, as used herein, refers to the radical —OH.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. Examples of protected group includes, butare not limited to, acetyl, tetrahydropyran, methoxymethyl ether,β-methoxyethoxymethyl ether, ρ-methoxybenzyl, methylthiomethyl ether,pivaloyl, silyl ether, carbobenzyloxy, benzyl, tert-butoxycarbonyl,ρ-methoxyphenyl, 9-fluorenylmethyloxycarbonyl, acetals, ketals, acylals,dithianes, methylesters, benzyl esters, tert-butyl esters, and silylesters. A comprehensive list of suitable protecting groups can be foundin T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, Inc. 1999.

“Unsubstituted or substituted” or “optionally substituted” as usedherein indicate the substituent bound on the available valance of anamed group or radical. “Unsubstituted” as used herein indicates thatthe named group or radical will have no further non-hydrogensubstituents. “Substituted” or “optionally substituted” as used hereinindicates that at least one of the available hydrogen atoms of namedgroup or radical has been (or may be) replaced by a non-hydrogensubstituent.

Unless otherwise specified, examples of substituents may include, butare not limited to, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,C₁₋₆alkoxy, 6- to 10-membered aryloxy, 5- to 10-membered heteroaryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, C₁₋₆alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, C₁₋₆alkyl, C₁₋₆haloalkyl,hydroxyC₁₋₆alkyl, carbonylC₁₋₆alkyl, thiocarbonylC₁₋₁₀alkyl,sulfonylC₁₋₆alkyl, sulfinylC₁₋₆alkyl, C₁₋₁₀azaalkyl, iminoC₁₋₆alkyl, 3-to 12-membered cycloalkylC₁₋₆alkyl, 4- to 15-memberedheterocycloalkylC₁₋₆alkyl, 6- to 10-membered arylC₁₋₆alkyl, 5- to10-membered heteroarylC₁₋₆alkyl, 10- to 12-memberedbicycloarylC₁₋₆alkyl, 9- to 12-membered heterobicycloarylC₁₋₆alkyl, 3-to 12-membered cycloalkyl, 4- to 12-membered heterocycloalkyl, 9- to12-membered bicycloalkyl, 3- to 12-membered heterobicycloalkyl, 6- to12-membered aryl, and 5- to 12-membered heteroaryl,

“Sulfonyl”, as used herein, means the radical —S(O)₂—. It is noted thatthe term “sulfonyl” when referring to a monovalent substituent canalternatively refer to a substituted sulfonyl group, —S(═O)₂R, where Ris hydrogen or a non-hydrogen substituent on the sulfur atom formingdifferent sulfonyl groups including sulfonic acids, sulfonamides,sulfonate esters, and sulfones.

are symbols denoting the point of attachment of the radical X, to otherpart of the molecule.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkoxyalkyl wouldrepresent an alkoxy group attached to the parent molecule through analkyl group.

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, aC₁alkyl indicates that there is one carbon atom but does not indicatewhat are the substituents on the carbon atom. Hence, a C₁alkyl comprisesmethyl (i.e., —CH₃) as well as —CR_(a)R_(b)R_(c) where R_(a), R_(b), andR_(c) may each independently be hydrogen or any other substituent wherethe atom attached to the carbon is not a hydrogen atom. Hence, —CF₃,—CH₂OH and —CH₂CN, for example, are all C₁alkyls.

“Chondrocytes” refers to cartilage cells. Chondrocytes produce andmaintain the cartilaginous matrix which is composed of collagen andproteoglycans. Chondrocytes are derived from the differentiation ofmesenchymal stem cells (MSCs). MSCs are multipotent stem cells that candifferentiate into several different types of cells including, but notlimited to, osteoblasts, chondrocytes and adipocytes. Differentiation isthe process a specialized cell type is formed from a less specializedcell type, for example, a chondrocyte from a MSC.

“Hyaluronic acid” refers to derivatives of hyaluronic acid that includeesters of hyaluronic acid, salts of hyaluronic acid and also includesthe term hyaluronan. The designation also includes both low and highmolecular weight forms of hyaluronans and crosslinked hyaluronans orhylans. Examples of such hyaluronans are Synvisc™ (Genzyme Corp.Cambridge, Mass.), ORTHOVISC™ (Anika Therapeutics, Woburn, Mass.), andHYALGAN™ (Sanofi-Synthelabo Inc., Malvern, Pa.).

Description of the Preferred Embodiments

The invention provides a novel class of compounds, pharmaceuticalcompositions comprising such compounds and methods of using suchcompounds to treat or prevent joint damage resulting from joint injuryand arthritis. In particular, the compounds can be used to treat acutejoint damage, osteoarthritis, traumatic arthritis, degenerative discdisease, and systemic rheumatoid arthritis.

I. Compounds of the Invention

In the first embodiment, the compound of the invention is of Formula I

or a pharmaceutically acceptable salt, or stereoisomer thereof; wherein

-   -   “-----” represents a single or double bond;    -   A is CR^(8a)R^(8b), NR⁹, or O; wherein R^(8a), R^(8b) and R⁹ are        each independently hydrogen or C₁₋₆alkyl;    -   L is *—C(O)NR¹⁰— or *—C(O)O—, wherein “*” represents the point        of attachment of L to the bicyclic ring containing A, and R¹⁰ is        hydrogen or C₁₋₆alkyl;    -   R⁰ is selected from hydrogen and C₁₋₆alkyl;    -   R¹ is selected from halo, cyano, —C(O)R¹¹, —C(O)NR^(12a)R^(12b),        —C(O)ONR^(12a)R^(12b), 5- and 6-membered heterocycloalkyl, 5-        and 6-membered heterocyclyl, phenyl, and 5- to 9-membered        heteroaryl, wherein        -   R¹¹ is hydrogen or C₁₋₆alkyl;        -   R^(12a) and R^(12b) are each independently hydrogen or            C₁₋₆alkyl;        -   the heterocycloalkyl, heterocyclyl, phenyl, or heteroaryl of            R¹ is unsubstituted or substituted by 1 to 2 substituents            independently selected from halo, cyano, C₁₋₆alkyl,            C₁₋₆haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b), 5- and            6-membered heterocycloalkyl, phenyl, and 5- and 6-membered            heteroaryl; wherein            -   R¹³ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,                amino, and C₁₋₆alkylamino;            -   R^(14a) and R^(14b) are each independently selected from                hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, —C(O)OR¹⁵, and —S(O)₂R¹⁵,                wherein R¹⁵ is hydrogen or C₁₋₆alkyl; and            -   the heterocycloalkyl, phenyl or heteroaryl substituent                of R¹ is further substituted by 1 to 2 substituents                independently selected from halo, C₁₋₆alkyl,                C₁₋₆haloalkyl, and hydroxy;    -   R³ is selected from C₁₋₆alkyl, C₁₋₆haloalkyl, 3- to 6-membered        cycloalkyl, (159), 4- to 7-membered heterocycloalkyl, 5- to        10-membered heterocyclyl, phenyl, and 5- to 9-membered        heteroaryl, wherein        -   the cycloalkyl, heterocycloalkyl, heterocyclyl, phenyl, or            heteroaryl of R³ is unsubstituted or substituted by 1 to 2            substituents independently selected from halo, cyano,            C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,            —C(O)R¹⁶, —C(O)OR¹⁶, —S(O)₂R¹⁶, 5 and 6 membered            heterocycloalkyl, and phenyl; wherein            -   R¹⁶ is hydrogen or C₁₋₆alkyl;            -   the phenyl or heterocycloalkyl substituent or R³ is                unsubstituted or further substituted by 1 to 2                substituents independently selected from halo, cyano,                C₁₋₆alkyl, and C₁₋₆haloalkyl; and    -   R² and R⁴ are each hydrogen or C₁₋₆alkyl; or R² and R⁴ taken        together form a cyclopropyl ring fused to the bicyclic ring        containing A; or R² and R⁴ taken together form a bond producing        a double bond between the two carbons to which R² and R⁴ are        attached; and    -   R⁵ is hydrogen or C₁₋₆alkyl, or R⁵ and R¹⁰ taken with the atoms        to which they are linked form a 5- or 6-membered ring fused to        the bicyclic ring containing A; and    -   R⁶ and R⁷ are each hydrogen or C₁₋₆alkyl; or R⁶ and R⁷ taken        together form a bond producing a double bond between the two        carbons to which R⁶ and R⁷ are attached.

In another embodiment, the compound is of Formula IA:

-   -   “-----” represents a single or double bond;    -   R⁰ is hydrogen or C₁₋₆alkyl;    -   R¹ is selected from cyano, —C(O)NR^(12a)R^(12b), 6-membered        heterocycloalkyl, 6-membered heterocyclyl, phenyl, and 5- to        9-membered heteroaryl, wherein        -   R^(12a) and R^(12b) are each independently hydrogen or            C₁₋₆alkyl;        -   the heterocycloalkyl, heterocyclyl, phenyl, or heteroaryl of            R¹ is unsubstituted or substituted by 1 to 2 substituents            independently selected from halo, cyano, C₁₋₆alkyl,            C₁₋₆haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b), 5- and            6-membered heterocycloalkyl, phenyl, and 5- and 6-membered            heteroaryl; wherein            -   R¹³ is selected from C₁₋₆alkyl, amino, and                C₁₋₆alkylamino;            -   R^(14a) and R^(14b) are each independently selected from                hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, —C(O)OR¹⁵, and —S(O)₂R¹⁵,                wherein R¹⁵ is hydrogen or C₁₋₆alkyl; and            -   the heterocycloalkyl, phenyl or heteroaryl substituent                of R¹ is unsubstituted or further substituted by 1 to 2                substituents independently selected from halo, hydroxy,                C₁₋₆alkyl, and C₁₋₆haloalkyl,    -   R³ is selected from C₁₋₆alkyl, C₁₋₆haloalkyl, 5- and 6-membered        cycloalkyl, (159), 5- and 6-membered heterocycloalkyl, 6- and        10-membered heterocyclyl, phenyl, and 5- and 6-membered        heteroaryl, wherein        -   the cycloalkyl, heterocycloalkyl, heterocyclyl, phenyl, or            heteroaryl of R³ is unsubstituted or substituted by 1 to 2            substituents independently selected from halo, cyano,            C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,            —C(O)R¹⁶, —C(O)OR¹⁶, —S(O)₂R¹⁶, 5- and 6-membered            heterocycloalkyl, and phenyl; wherein            -   R¹⁶ is hydrogen or C₁₋₆alkyl;            -   the phenyl or heterocycloalkyl substituent of R³ is                unsubstituted or further substituted by 1 to 2                substituents independently selected from halo, and                cyano; and    -   R² and R⁴ are independently hydrogen or C₁₋₆alkyl; or R² and R⁴        taken together form a cyclopropyl ring fused to the bicyclic        ring; or R² and R⁴ taken together form a bond producing a double        bond between the two carbons to which R² and R⁴ are attached;        and    -   R⁵ is hydrogen or C₁₋₆alkyl, or R⁵ and R¹⁰ taken with the atoms        to which they are linked form a 5- or 6-membered ring fused to        the bicyclic ring, and    -   R⁶ and R⁷ are independently hydrogen or C₁₋₆alkyl; or R⁶ and R⁷        taken together form a bond producing a double bond between the        two carbons to which R⁶ and R⁷ are attached.

In another embodiment of the compound of the invention, in accordance tothe embodiments above, R⁶ is hydrogen.

In another embodiment of the compound of the invention, in accordance toany one of the embodiments above, R⁷ is hydrogen.

In another embodiment, in accordance to any one of the embodimentsabove, the compound of the invention is of a formula selected from oneof the formulae below:

In another embodiment, in accordance to the first or second embodiment,the compound of the invention is of Formula IA1:

In yet another embodiment, in accordance to the first or secondembodiment, the compound of the invention is of Formula IA2:

In a yet another embodiment, in accordance to the first or secondembodiment, the compound of the invention is of Formula IA3:

In still another embodiment, in accordance to the first or secondembodiment, the compound of the invention is of Formula IA4:

In yet another embodiment of the compound of the invention, inaccordance to any one of the embodiments above, R⁰ is hydrogen.

In yet another embodiment of the compound of the invention, inaccordance to any one of the embodiments above, R⁵ is hydrogen.

In yet another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R¹ is selected from6-membered heterocycloalkyl, 6-membered heterocyclyl, phenyl, and 5- to9-membered heteroaryl, wherein the heterocycloalkyl, heterocyclyl,phenyl, or heteroaryl is unsubstituted or substituted by 1 to 2substituents independently selected from halo, cyano, C₁₋₆alkyl,C₁₋₆haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b), 5- and 6-memberedheterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein

-   -   R¹³ is selected from C₁₋₆alkyl, amino, and C₁₋₆alkylamino;    -   R^(14a) and R^(14b) are each independently selected from        hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, —C(O)OR¹⁵, and —S(O)₂R¹⁵, wherein        R¹⁵ is C₁₋₆alkyl; and    -   the heterocycloalkyl, phenyl or heteroaryl substituent of R¹ is        unsubstituted or further substituted by 1 to 2 substituents        independently selected from halo, hydroxy, C₁₋₆alkyl and        C₁₋₆haloalkyl.

In another embodiment of the compound of the invention, in accordance toany one of the above embodiments, R¹ is phenyl, 5- or 6-memberedheteroaryl, wherein the phenyl or heteroaryl is unsubstituted orsubstituted by 1 to 2 substituents independently selected from halo,cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b),5- and 6-membered heterocycloalkyl, phenyl, and 5- and 6-memberedheteroaryl, wherein

-   -   R¹³ is selected from C₁₋₆alkyl, amino, and C₁₋₆alkylamino;    -   R^(14a) and R^(14b) are each independently selected from        hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, and —C(O)OR¹⁵, wherein R¹⁵ is        C₁₋₆alkyl; and    -   the heterocycloalkyl, phenyl or heteroaryl substituent of R¹ is        unsubstituted or further substituted by 1 to 2 substituents        independently selected from hydroxy, halo, C₁₋₆alkyl, and        C₁₋₆haloalkyl.

In another embodiment of the compound of the invention, in accordance toany one of the above embodiments, R¹ is selected from cyano, —C(O)NH₂,piperidinyl, tetrahydropyridinyl, dihydropyranyl, phenyl, pyrazoyl,oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and Indazolyl, whereinthe piperidinyl, tetrahydropyridinyl, dihydropyranyl, phenyl, pyrazoyl,oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or Indazolyl isunsubstituted or substituted by 1 to 2 substituents independentlyselected from halo, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, —C(O)R¹³,—C(O)OR¹³, —NR^(14a)R^(14b), 5- and 6-membered heterocycloalkyl, phenyl,and 5- and 6-membered heteroaryl, wherein

-   -   R¹³ is selected from C₁₋₆alkyl, amino, and C₁₋₆alkylamino;    -   R^(14a) and R^(14b) are each independently selected from        hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, —C(O)OR¹⁵, and —S(O)₂R¹⁵, wherein        R¹⁵ is C₁₋₆alkyl; and    -   the heterocycloalkyl, phenyl or heteroaryl substituent of R¹ is        unsubstituted or further substituted by 1 to 2 substituents        independently selected from hydroxy, halo, C₁₋₆alkyl, and        C₁₋₆haloalkyl.

In another embodiment of the compound of the invention, in accordance toany one of the above embodiments, R¹ is selected from pyrazoyl,oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, wherein thepyrazoyl, oxadiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl isunsubstituted or substituted by 1 to 2 substituents independentlyselected from halo, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, —C(O)R¹³,—C(O)OR¹³, —NR^(14a)R^(14b), 5- and 6-membered heterocycloalkyl, andphenyl, wherein

-   -   R¹³ is selected from C₁₋₆alkyl, amino, and C₁₋₆alkylamino;    -   R^(14a) and R^(14b) are each independently selected from        hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, and —C(O)OR¹⁵, wherein R¹⁵ is        C₁₋₆alkyl; and    -   the heterocycloalkyl or phenyl substituent of R¹ is        unsubstituted or further substituted by 1 to 2 substituents        independently selected from hydroxy, halo, C₁₋₆alkyl, and        C₁₋₆haloalkyl.

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R¹ is selected frompyrazoyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which isunsubstituted or substituted by 1 to 2 substituents independentlyselected from halo, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, —C(O)R¹³,—C(O)OR¹³, NR^(14a)R^(14b), tetrahydropyranyl, hydroxy substitutedpyrrolidinyl, wherein

-   -   R¹³ is C₁₋₆alkyl, amino, or C₁₋₆alkylamino;    -   R^(14a) and R^(14b) are each independently selected from        hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, and —C(O)OR¹⁵, wherein R¹⁵ is        C₁₋₆alkyl.

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R¹ is selected from

wherein “*” represents the point of attachment of R¹ to the bicycliccore ring.

In still another embodiment of the compound of the invention, inaccordance to any one of the above first to eleventh embodiments, R¹ isselected from

wherein “*” represents the point of attachment of R¹ to the bicycliccore ring.

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R¹ is

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R¹ is

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R¹ is

In

Still another embodiment of the compound of the invention, in accordanceto any one of the above embodiments, R¹ is

In another embodiment of the compound of the invention, in accordance toany one of the above embodiments, R¹ is

In another embodiment of the compound of the invention, in accordance toany one of the above embodiments, R¹ is

In another embodiment of the compound of the invention, in accordance toany one of the above embodiments, R¹ is

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R¹ is

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R¹ is

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R³ is phenyl, 5- or6-membered heteroaryl, wherein

-   -   the phenyl, or heteroaryl of R³ is unsubstituted or substituted        by 1 to 2 substituents independently selected from halo, cyano,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —C(O)R¹⁶,        —C(O)OR¹⁶, —S(O)₂R¹⁶, 5- and 6-membered heterocycloalkyl, and        phenyl; wherein        -   R¹⁶ is C₁₋₆alkyl; and        -   the phenyl or heterocycloalkyl substituent or R³ is            unsubstituted or further substituted by 1 to 2 substituents            independently selected from halo or cyano.

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R³ is selected fromcyclohexyl, piperidinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, phenyl,pyrazolyl, pyridinyl, pyrimidinyl, wherein the cyclohexyl, piperidinyl,2,3-dihydrobenzo[b][1,4]dioxinyl, phenyl, pyrazolyl, pyridinyl, orpyrimidinyl is unsubstituted or substituted by 1 to 2 substituentsindependently selected from halo, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, —C(O)R¹⁶, —C(O)OR¹⁶, —S(O)₂R¹⁶, 5- and6-membered heterocycloalkyl, and phenyl; wherein

-   -   R¹⁶ is C₁₋₆alkyl; and    -   the phenyl or heterocycloalkyl substituent or R³ is        unsubstituted or further substituted by 1 to 2 substituents        independently halo or cyano.

In still another embodiment of the compound of the invention, inaccordance to any one of the embodiments, R³ is selected from:

wherein “*” represents the point of attachment of R³ to the bicyclicring.

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R³ is selected from:

wherein “*” represents the point of attachment of R¹ to the bicycliccore ring.

In still another embodiment of the compound of the invention, inaccordance to any one of the above embodiments, R³ is

In still another embodiment, R³ is

In still another embodiment, R³ is

In still another embodiment, R³ is

In still another embodiment, R³ is

In still another embodiment, R³ is

In still another embodiment, R³ is

In still another embodiment, R³ is

In still another embodiment, R³ is

In still another embodiment, R³ is

In still another embodiment of the compound of the invention, inaccordance to any one of the above first to forth-first embodiments, R¹⁰is hydrogen.

In a special embodiment, the compound of the invention is of Formula IB:

or a pharmaceutically acceptable salt, or an enantiomer thereof, or amixture of the respective enantiomers thereof, wherein

-   -   “-----” represents a single or double bond;    -   R¹ is phenyl, 5- or 6-membered heteroaryl, wherein        -   the phenyl or heteroaryl of R¹ is unsubstituted or            substituted by 1 to 2 substituents independently selected            from halo, cyano, C₁₋₆alkyl, C₁₋₄haloalkyl, —C(O)R¹³,            —C(O)OR¹³, —NR^(14a)R^(14b), 5- and 6-membered            heterocycloalkyl, phenyl, and 5- and 6-membered heteroaryl,            wherein            -   R¹³ is C₁₋₆alkyl or amino;            -   R^(14a) and R^(14b) are independently is selected from                hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, and —C(O)OR¹⁵, wherein                R¹⁵ is C₁₋₄alkyl; and            -   the heterocycloalkyl, phenyl, or heteroaryl substituent                of R¹ is unsubstituted or substituted by 1 to 2                substituents independently selected from halo, hydroxy,                and C₁₋₆alkyl;    -   R³ is phenyl, 5- or 6-membered heteroaryl, wherein the phenyl or        heteroaryl is unsubstituted or substituted by 1 to 2        substituents independently selected from halo, cyano, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —C(O)R¹⁶, —C(O)OR¹⁶,        5- and 6-membered heterocycloalkyl, and phenyl, wherein        -   R¹⁶ is C₁₋₆alkyl; and        -   the heterocycloalkyl or phenyl is unsubstituted or            substituted by 1 to 2 substituents selected from halo and            cyano;    -   R² and R⁴ are independently hydrogen or C₁₋₆alkyl, or R² and R⁴        taken together form a cyclopropyl fused to the bicyclic ring, or        R² and R⁴ taken together form a bond, producing a double bond        between the two carbons to which R² and R⁴ are attached.

In some embodiment according to the special embodiment above, thecompound of the invention is of a formula selected from Formulae:

It is noted that the compounds of the invention may possess asymmetriccarbon atoms (optical centers) or double bonds; the enantiomers,diastereomers, geometric isomers and individual stereoisomers, andmixtures of the stereoisomers are all intended to be encompassed withinthe scope of the present invention. Particularly, the present inventioncontemplates that the compounds of the invention may be obtained andused as individual diastereomers which may be obtained and used asenantiomerically enriched mixtures of two enantiomers, or occasionallyas a single enantiomer. In some embodiments of the invention, a formulashown herein as a single stereoisomer includes the enantiomer of thedepicted compound and mixtures of the enantiomers unless otherwisespecified. Where a compound is described as a single diastereomer or asingle enantiomer, it is understood that a sample of the compound maystill contain small amounts of other diastereomers or of the oppositeenantiomer. Typically, where a compound is described as a single isomer,diastereomer or enantiomer, the specified structure accounts for atleast 90% by weight of total weight of depicted compound plus itsisomers; preferably, the specified isomer, diastereomer or enantiomeraccounts for at least 95% by weight of the total weight including otherisomers.

The compounds of the invention In the present application, thestereoisomers are identified by their structural formula, a diastereomeridentifier and an enantioisomer identifier. For example, Formula IB1a′identifies the compound is of Formula IB1 (see supra), the “a” denotes aspecific diastereomer, and the “′” or “″” denotes a specific enantiomer.Further, for ease of presentation, the compounds are represented by thestructure or name of one of the enantiomers, but unless otherwiseindicated, the structure or name designates an enantiomeric mixture.

In some embodiments according to the special embodiment above, thecompound of the invention is selected from the stereoisomers of FormulaIB1 including:

In some other embodiments according to the above special embodiment, thecompound of the invention is selected from the stereoisomers of FormulaIB2 including:

In some other embodiments according to the above special embodiment, thecompound of the invention is selected from the stereoisomer of FormulaIB3 including:

In some other embodiments, the compound of the invention is selectedfrom the single stereoisomer of Formula IB including:

In some other embodiments, the compound of the invention is selectedfrom a single stereoisomer of Formula IB including:

In an embodiment according to the above special embodiment, the compoundof the invention is a single stereoisomer of Formula IB1a″

In another embodiment, the compound of the invention is a singlestereoisomer of Formula IB1b′

In another embodiment, the compound of the invention is a singlestereoisomer of Formula IB1b″

In another embodiment, the compound of the invention is a singlestereoisomer of Formula IB1c′

In another embodiment, the compound of the invention is a singlestereoisomer of Formula IB1d′

In another embodiment, the compound of the invention is a singlestereoisomer of Formula IB1d″

In another embodiment, the compound of the invention is a singlestereoisomer of Formula IB2′

In another embodiment, the compound of the invention is a singlestereoisomer of Formula IB2″

In another embodiment, the compound of the invention is of Formula IB3b′

In another embodiment, the compound of the invention is a singlestereoisomer of Formula IB3b″

In one embodiment of the compound of the invention, according to any oneof the above special embodiment and other embodiments, R¹ is a 5 or 6membered heteroaryl, unsubstituted or substituted by 1 to 2 substituentsindependently selected from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, andNHR^(14b), wherein R^(14b) is hydrogen or C₁₋₄alkyl.

In another embodiment of the compound of the invention according to anyone of the above special embodiment and other embodiments, R¹ isselected from pyrazolyl, oxadiazolyl, pyridinyl, pyrimidinyl andpyrazinyl, wherein the pyrazolyl, pyridinyl, pyrimidinyl or pyrazinyl isunsubstituted or substituted by —NH₂, —NHC(O)OCH₃ or trifluoromethyl.

In another embodiment of the compound of the invention according to anyone of the above special embodiment and other embodiments, R¹ isselected from

wherein “*” represents the point of attachment of R¹ to the bicycliccore ring.

In still another embodiment of the compound of the invention accordingto any one of the above special embodiment and other embodiments, R³ isphenyl substituted by 1 to 2 substituents independently selected fromhalo, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, andphenyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —C(O)R¹⁶,—C(O)OR¹⁶, wherein R¹⁶ is C₁₋₆alkyl, and the phenyl substituent of R³ isunsubstituted or further substituted by 1 to 2 substituentsindependently selected from halo and cyano.

In still another embodiment of the compound of the invention accordingto any one of the above special embodiment and embodiments, R³ isselected from

wherein “*” represents the point of attachment of R¹ to the bicycliccore ring.

Particular examples of the compounds, or a pharmaceutically acceptablesalt thereof, or the corresponding enantiomer thereof, according to thepresent invention include, but are not limited to:(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(2-(ethylsulfonamido)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl2-((1R,2S,3R,4S)-3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(1H-pyrazol-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3S,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2R,3R,4R)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;methyl4-((1R,2S,3R,4S)-3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)-[1,1′-biphenyl]-3-carboxylate;(1S,2S,3R,4R)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-1H-pyrazol-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3S,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(2-(N-propionylpropionamido)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;methyl(4-((1S,2S,3R,4R)-3-((3,4-dichlorophenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)carbamate;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(2-propionamidopyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl4-((1R,2S,3R,4S)-3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,2R,3R,4S)—N-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(2-(dimethylamino)pyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)-3-(2-cyanopyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,4S)—N-(2-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-3-(1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyrimidin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(2-(dimethylamino)pyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;

methyl5-chloro-2-((1R,2S,3R,4S)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,2S,3S,4S)-3-(4-carbamoylphenyl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(2-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)-3-(5-aminopyridin-3-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,4S)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-4-yl)-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1S,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2S,3R,4S)—N-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3S,4S)—N-(3,4-dichlorophenyl)-3-(2-(dimethylamino)pyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)-3-(4-carbamoylphenyl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(3aR,6R,7S,7aS)-2-([1,1′-biphenyl]-4-yl)-7-(pyridin-4-yl)-2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-1(6H)-one;(1R,2R,3S,4S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,4R)—N-(2-phenylpyrimidin-5-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2S,3R,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)-3-(6-aminopyridin-3-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(3-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)-3-(2-cyanopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl2-fluoro-4-(3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamido)benzoate;(1S,4S)-3-(2-chloropyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;ethyl5-((1S,2S,3S,4R)-3-((3,4-dichlorophenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)nicotinate;(1S,4S)-3-cyano-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;ethyl5-((1S,2S,3R,4R)-3-((3,4-dichlorophenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)nicotinate;(1S,4S)-3-(2-aminopyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1S,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1S,4S)—N-(2-fluoro-3-(trifluoromethoxy)phenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2S,3R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyrimidin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;methyl5-chloro-2-((1S,4S)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamido)benzoate;(1R,2S,3S,4S)—N-([1,1′-biphenyl]-4-yl)-3-(pyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,4S)-3-(2-cyanopyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2R,3S,4S)—N-([1,1′-biphenyl]-4-yl)-3-(pyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl2-morpholino-4-((1R,2S,3R,4S)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,2S,3S,4S)-3-(2-cyanopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)-3-cyano-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,4S)—N-(5-methyl-1-phenyl-1H-pyrazol-3-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1S,4R)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2S,3S,4S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)-3-(2-aminopyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(2-methyl-2H-indazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3S,4S)-3-(6-aminopyridin-3-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl2-fluoro-4-((1S,4R)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamido)benzoate;(1R,2R,3S,4S)-3-(6-acetamidopyridin-3-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)-3-(pyridin-4-yl)-N-(2,2′,4′-trifluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;tert-butyl4-((1S,2S,3S,4R)-3-((3,4-dichlorophenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate;(1R,2R,3R,4S)—N-([1,1′-biphenyl]-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,4S,5S)—N-(4′-chloro-2′-cyano-2-fluoro-[1,1′-biphenyl]-4-yl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide;(1R,2R,3S,4S)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2S,3R,4R)-3-cyano-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(2-(dimethylamino)pyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,4S,5S)—N-([1,1′-biphenyl]-4-yl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide;(1R,2R,3S,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3S,4S)—N-(3,4-dichlorophenyl)-3-(3,6-dihydro-2H-pyran-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3S,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,4S,5S)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-4-yl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide;(1R,2R,3S,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)-3-(2,6-dichloropyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;tert-butyl4-((1S,2S,3R,4R)-3-((3,4-dichlorophenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,4S,5S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide;(1R,2R,3S,4S)-3-(2-aminopyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-1,4-dimethyl-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)-3-(3-chloro-2-fluoropyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,4S,5S)—N-(2-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide;(1S,4S)-3-(3-chloro-2-fluoropyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2R,3S,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)-3-(2-chloropyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2R,3R,4R)-3-cyano-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3S,4S)-3-(pyridin-4-yl)-N-(2,2′,4′-trifluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2S,3R,4R)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;1R,2S,3S,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl4-((1R,2R,3S,4S)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,2R,3S,4S)-3-(2-aminopyridin-4-yl)-N-(2-chloro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,4S,5S)—N-(3,4-dichlorophenyl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide;(1S,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(3-fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2S,3S,4S)-3-(2-aminopyridin-4-yl)-N-(2-chloro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3S,4S)-3-(pyridin-4-yl)-N-(2,2′,4′-trifluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2R,3S,4R)—N2-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxamide;(1R,2R,4S,5S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide;(1R,2R,4S,5S)—N-(2′-chloro-2-cyano-[1,1′-biphenyl]-4-yl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide;(1R,2S,3S,4S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,4S)-3-(2,6-dichloropyridin-4-yl)-N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(3,6-dihydro-2H-pyran-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl4-((1R,2S,3S,4S)-3-(2-aminopyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,2R,3S,4S)—N-([1,1′-biphenyl]-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2S,3S,4R)—N-([1,1′-biphenyl]-4-yl)-3-(pyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2S,3S,4R)—N-([1,1′-biphenyl]-4-yl)-3-(1-methyl-1H-pyrazol-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2S,3S,4R)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(1-methylpiperidin-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(2-fluoro-3-(trifluoromethyl)phenyl)-3-((2R)-6-(trifluoromethyl)piperidin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl4-((1S,2S,3R,4S)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;ethyl3-((1R,2S,3R,4S)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,2S,3R,4S)—N-(2-fluoro-3-(trifluoromethoxy)phenyl)-3-(4-methylpyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl4-((1S,4S)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamido)benzoate;(1S,4S)—N-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1S,2S,3R,4S)—N-(1-(methylsulfonyl)piperidin-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;methyl5-chloro-2-((1S,2S,3R,4S)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1S,2S,3R,4S)-3-(pyridin-4-yl)-N-(3-(trifluoromethoxy)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,4S)—N-(3,4-dichlorophenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1S,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;methyl4-fluoro-3-((1S,2S,3R,4S)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1S,2S,3R,4S)-3-(pyridin-4-yl)-N-(4-(trifluoromethoxy)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2R,3R,4S)—N-(3,4-dichlorophenyl)-3-(pyrazin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;ethyl4-((1R,4S)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamido)benzoate;(1R,2R,3R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,4S)—N-(3,4-dichlorophenyl)-3-(pyrazin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2S,3R,4S)—N-(5-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(1-acetylpiperidin-4-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(4-chloro-3-fluorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(4-chloro-2-cyanophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl4-((1R,2S,3R,4S)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;ethyl4-((1R,2S,3R,4S)-3-(5-methoxypyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,2R,3R,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(2-fluoro-3-(trifluoromethoxy)phenyl)-3-(4-methylpyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(3,4-dichlorophenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,4S)—N-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;ethyl4-((1R,2R,3R,4S)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;(1R,2S,3R,4S)—N-cyclohexyl-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2S,3R,4S)—N-(5-chloro-4-methylpyridin-2-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(pyrazin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide,(1R,2S,3R,4S)—N-(3-chloro-2-fluorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(4-methylpyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)pyridin-4-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide;(1R,2R,3R,4S)—N-(2-fluoro-3-(trifluoromethyl)phenyl)-3-(pyrazin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(5-chloropyridin-2-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(4-methylpyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(2-fluoro-3-(trifluoromethoxy)phenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2R,3R,4S)—N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,3R,4S)—N-(4-chloropyridin-2-yl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;ethyl4-((1R,2R,3R,4S)-3-(pyrazin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamido)benzoate;and(1R,2S,3R,4S)—N-(4-cyanophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt. It is further note that thecompound of the present invention may comprise a single enantiomer, or amixture of the corresponding enantioments.

Further compounds of the invention are detailed in the Examples, infra.

As used herein, the term “an optical isomer” or “a stereoisomer” refersto any of the various stereo isomeric configurations which may exist fora given compound of the present invention and includes geometricisomers. It is understood that a substituent may be attached at a chiralcenter of a carbon atom. The term “chiral” refers to molecules whichhave the property of non-superimposability on their mirror imagepartner, while the term “achiral” refers to molecules which aresuperimposable on their mirror image partner. Therefore, the inventionincludes enantiomers, diastereomers or mixture of the correspondingenantiomers, and racemates of the compound. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other.Generally, a 1:1 mixture of a pair of enantiomers is a “racemic”mixture. The term is used to designate a racemic mixture whereappropriate. “Diastereoisomers” are stereoisomers that have at least twoasymmetric atoms, but which are not mirror-images of each other. Theabsolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain compounds described herein contain one ormore asymmetric centers or axes and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)— or (S)—.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possible isomers oras mixtures thereof, for example as pure optical isomers, or as isomermixtures, such as racemates and diastereoisomer mixtures, depending onthe number of asymmetric carbon atoms. The present invention is meant toinclude all such possible isomers, including diasteriomeric mixturesenantiomers mixture, and optically pure forms. Optically active (R)- and(S)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques. If the compound contains adouble bond, the substituent may be E or Z configuration. If thecompound contains a disubstituted cycloalkyl, the cycloalkyl substituentmay have a cis- or trans-configuration. All tautomeric forms are alsointended to be included.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturateddouble bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Methods for the determination of stereochemistry and the separation ofstereoisomers are well known in the art (e.g., see “Advanced OrganicChemistry”, 4th edition, March, Jerry, John Wiley & Sons, New York,1992). Any resulting mixtures of isomers can be separated on the basisof the physicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as 3H and 14C, or those into which non-radioactiveisotopes, such as ²H and ¹³C are present. Such isotopically labelledcompounds are useful in metabolic studies (with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques,such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically-labeled compounds of formula (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

II. Preparation of the Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Synthesis”, John Wiley and Sons, 1991.

Typically, the compounds of formula (I) can be prepared according tosynthetic routes 1-6 provided infra., where R¹ and R³ and the formulaeare as defined in the Detailed Description of the Invention. Thefollowing reaction schemes are given to be illustrative, not limiting,descriptions of the synthesis of compounds of the invention. Detaileddescriptions of the synthesis of compounds of the invention are given inthe Examples, infra.

Reaction conditions:

-   -   a. Intermediate I-1 can be prepared from methyl propiolate by        bromination, followed by Diels-Alder reaction with furan.        Methods for the bromination are known, using N-bromosuccinimide        or similar brominating agents in the presence of a silver        catalyst, such as silver nitrate in a polar solvent such as        acetone or MEK. The Diels-Alder cycloaddition occurs with mild        heating (ca. 80° C.) in excess furan.    -   b. Compound I-2 can be prepared by hydrogenation of I-1 using a        palladium catalyst under a low hydrogen pressure in a non-protic        solvent such as ethyl acetate.    -   c. Compound I-3 can be prepared from I-2 by hydrolysis of the        methyl ester under conventional conditions, followed by        formation of the t-butyl ester. Hydrolysis occurs under mild        conditions using aqueous base (e.g., lithium hydroxide, room        temperature) in a solvent mixture typically containing an        alcohol and a water-miscible co-solvent such as THF. Formation        of the t-butyl ester can be accomplished under known conditions        such as mild heating (e.g., 40-80° C.) with excess DMF        di-t-butyl acetal in toluene.    -   d. Compound I-3 is conveniently debrominated to compound I-4        using a dissolving metal reduction, such as reaction with zinc        in mildly acidic aqueous mixture. A suitable co-solvent such as        THF is used, and a mild acid such as formic or acetic acid. The        reaction can be conducted at 0° C. to room temperature.    -   e. The t-butyl ester of compound I-4 can be hydrolyzed under        acidic conditions, using a strong acid such as hydrochloric,        sulfuric or phosphoric acid in a suitable polar aprotic solvent        such as dioxane, to produce the free carboxylic acid.        Conventional amide formation conditions can be used to make the        amide I-5. For example, the carboxylic acid can be treated with        a desired aniline and a dehydrating agent such as a carbodiimide        (DCC, EDCI) and catalytic DMAP in pyridine.    -   f. Arylation of compound I-5 with an aryl boronate ester can be        achieved with a rhodium dimer catalyst and BINAP with aqueous        base in dioxane, with microwave heating at about 100° C.        Arylation provides a mixture of cis and trans isomers that can        be separated; the trans isomer is typically the major product,        with the aryl group added syn to the ether bridge of the        product.

Reaction Conditions:

-   -   a. Compound I-2, made in General Synthetic Route 1, can be        de-brominated with zinc in aqueous acetic acid under mild        conditions, e.g., 0° C. to room temperature.    -   b-c or d. The arylation of compound I-7 with an aryl boronate        ester is conducted with a dimeric rhodium catalyst plus BINAP        and an aqueous base in dioxane, with microwave heating at about        100° C. Arylation provides a mixture of cis and trans isomers        that can be separated; the trans isomer is typically the major        product, with the aryl group added syn to the ether bridge of        the product. Hydrolysis to the free carboxylic acid can be        achieved with aqueous base and an organic co-solvent either in        the same pot as the arylation, or the ester can be isolated and        then hydrolyzed in a separate step.    -   e. Formation of the amide product can be accomplished using        known amide formation conditions, such as treating the acid plus        the desired aniline or amine with T3P (propyl phosphonic        anhydride) and an amine base (diisopropyl ethylamine,        triethylamine) in organic solvent such as ethyl acetate plus        DMF, at room temperature or at elevated temperature up to about        100° C.

General Synthetic Route 3

Reaction Conditions:

-   -   a. Intermediate 5a can be prepared from intermediate I-2 using        standard Suzuki coupling conditions. Typically a mixture or        bromide, boronic ester, base, and tetrakis in 3:1        1,4-dioxane:water was warmed (ca. 100° C.) for 30 minutes in a        microwave reactor.    -   b. Compound 5b can be prepared from 5a by hydrolysis of the        methyl ester under conventional conditions. Hydrolysis occurs        under mild conditions using aqueous base (e.g., lithium        hydroxide, room temperature) in a solvent mixture typically        containing an alcohol and a water-miscible co-solvent such as        THF.    -   c. Formation of the amide product can be accomplished using        known amide formation conditions, such as treating the acid plus        the desired aniline or amine with T3P (propyl phosphonic        anhydride) and an amine base (diisopropyl ethylamine,        triethylamine) in organic solvent such as ethyl acetate at room        temperature or at elevated temperature up to about 80° C.    -   d. Compound IB1d can be prepared by hydrogenation of IB2 using a        palladium catalyst under a low hydrogen pressure in a solvent        such as ethyl acetate.    -   e. Compound IB1b (enantiomers IB1b′ and IB1b″) can be prepared        by warming (ca. 80° C.) a solution of IB1d in morpholine.

Reaction Conditions:

-   -   a. Intermediate 5a can be prepared from intermediate I-2 using        standard Suzuki coupling conditions. Typically a mixture or        bromide, boronic ester, base, and tetrakis in 3:1        1,4-dioxane:water was warmed (ca. 100° C.) for 30 minutes in a        microwave reactor.    -   b. Compound 5b can be prepared from 5a by hydrolysis of the        methyl ester under conventional conditions. Hydrolysis occurs        under mild conditions using aqueous base (e.g., lithium        hydroxide, room temperature) in a solvent mixture typically        containing an alcohol and a water-miscible co-solvent such as        THF.    -   c. Formation of the amide product can be accomplished using        known amide formation conditions, such as treating the acid plus        the desired aniline or amine with T3P (propyl phosphonic        anhydride) and an amine base (diisopropyl ethylamine,        triethylamine) in organic solvent such as ethyl acetate at room        temperature or at elevated temperature up to about 80° C.    -   d. Compound IB1d (enantiomers IB1d′ and IB1d″) can be prepared        by hydrogenation of IB2 using a palladium catalyst under a low        hydrogen pressure in a solvent such as ethyl acetate.

Reaction Conditions:

-   -   a. Intermediate 5a can be prepared from intermediate I-2 using        standard Suzuki coupling conditions. Typically a mixture or        bromide, boronic ester, base, and tetrakis in 3:1        1,4-dioxane:water was warmed (ca. 100° C.) for 30 minutes in a        microwave reactor.    -   b. Compound 5b can be prepared from 5a by hydrolysis of the        methyl ester under conventional conditions. Hydrolysis occurs        under mild conditions using aqueous base (e.g., lithium        hydroxide, room temperature) in a solvent mixture typically        containing an alcohol and a water-miscible co-solvent such as        THF.    -   c. Formation of the amide product can be accomplished using        known amide formation conditions, such as treating the acid plus        the desired aniline or amine with T3P (propyl phosphonic        anhydride) and an amine base (diisopropyl ethylamine,        triethylamine) in organic solvent such as ethyl acetate at room        temperature or at elevated temperature up to about 80° C.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure material.

Reaction Conditions:

-   -   a. Intermediate 6b can be prepared from intermediate 6a using        known cyclopropanation conditions. Typically a mixture of        trimethylsulfoxonium iodide in a solvent such as DMSO was        treated with NaH followed by 6a and gently warmed (ca. 50° C.)        overnight.    -   b. Compound 6c can be prepared from 6b by conventional        deprotection conditions.

Typically a solution of 6b in a solvent such as DCM was treated with TFAand stirred at room temperature.

-   -   c. Formation of IB3b can be accomplished using known amide        formation conditions, such as treating the acid plus the desired        aniline or amine with HATU        (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxide hexafluorophosphate) and an amine base (diisopropyl        ethylamine, triethylamine) in organic solvent such as EtOAc at        room temperature or at elevated temperature up to about 80° C.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

III. Methods of Therapeutic Use of the Compounds and Composition of theInvention, and Indications

The present invention provides a method of treating, ameliorating orpreventing arthritis of joint injury in a mammal in need thereof, themethod including administering to the mammal a therapeutically effectiveamount of a compound of the invention, wherein the subject has or is atrisk of joint damage or arthritis. The invention also provides a methodof treating, ameliorating or preventing arthritis or joint injury in ahuman patient, the method comprising: administering to a joint of thepatient a composition comprising an effective amount of a compound ofthe invention, thereby treating, ameliorating or preventing arthritis orjoint injury in the patient. In some embodiments, the patient hasarthritis or joint injury. In some embodiments, the individual does nothave, but is at risk for, arthritis or joint injury. In someembodiments, the arthritis is osteoarthritis, trauma arthritis, orautoimmune arthritis. In some embodiments, the composition administeredto the further comprises hyaluronic acid.

The compounds of the present invention are also useful for inducingdifferentiation of mesenchymal stem cells (MSCs) into chondrocytes. Insome embodiment, the present invention provides a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodincluding contacting mesenchymal stem cells with a sufficient amount ofa compound of the invention, thereby inducing differentiation of thestem cells into chondrocytes.

MSCs are multipotent stem cells that can differentiate into severaldifferent types of cells including, but not limited to, osteoblasts,chondrocytes and adipocytes. Differentiation is the process by which aspecialized cell type is formed from a less specialized cell type, forexample, a chondrocyte from a MSC. In some embodiments, the method isperformed in vitro. In some embodiments, the method is performed in vivoin a mammal and the stem cells are present in the mammal.

In some embodiment, the contacting occurs in a matrix or biocompatiblescaffold. In some embodiment, contacting the compound occurs inconjunction with one or more additional chondrogenic factors. In otherembodiment, contacting the compound occurs in conjunction with an agentselected from angiopoietin-like 3 protein (ANGPTL3), oral salmoncalcitonin, SD-6010 (iNOS inhibitor), vitamin D3 (cholecalciferol),collagen hydrolyzate, FGF18, BMP7, rusalatide acetate, avocado soyunsaponifiables (ASU), a steroid, and a non-steroidal anti-inflammatoryagent (NSAID) and hyaluronic acid.

Inducing differentiation of MSCs into chondrocytes can be accomplishedusing any suitable amount of a compound of the present invention. Insome embodiment, the compound of the present invention can be present inan amount form about 0.1 mg to about 10000 mg, e.g., 1.0 mg to 1000 mg,e.g., 10 mg to 500 mg, according to the particular application andpotency of the active component. In some embodiments, the compound ofthe present invention can be present in a concentration of 0.1 μM to toabout 100 μM, in an intraarticular injection to the knee.

It is contemplated that compounds, compositions, and methods of thepresent invention may be used to treat, ameliorate or prevent any typeof articular cartilage damage (e.g., joint damage or injury) including,for example, damage arising from a traumatic event or tendon or ligamenttear. In some embodiments, the compounds or compositions of theinvention are administered to prevent or ameliorate arthritis or jointdamage, for example where there is a genetic or family history ofarthritis or joint damage or joint injury or prior or during jointsurgery. In some embodiments, compounds, compositions and methods areused to treat joint damage. In particular embodiments, the joint damageis traumatic joint injury. In other embodiments, the joint damage isdamage arising from age or inactivity. In yet other embodiments, thejoint damage is damage arising from an autoimmune disorder. In someembodiments of the invention, compounds, compositions, and methods ofthe present invention may be used to treat, ameliorate or preventosteoarthritis. In some embodiments, the compounds, compositions andmethods are used to ameliorate or prevent arthritis in a subject at riskof having or acquiring arthritis. In some embodiments, the compounds,compositions and methods are used to ameliorate or prevent joint damagein a subject at risk of having or acquiring joint damage.

In some embodiments, compounds, compositions, and methods of the presentinvention provide a method for stimulating chondrocyte proliferation andcartilage production in cartilagenous tissues that have been damaged,e.g., due to traumatic injury or chondropathy. In particular embodimentscompounds, compositions, and methods of the present invention are usefulfor treatment of cartilage damage in joints, e.g., at articulatedsurfaces, e.g., spine, shoulder, elbow, wrist, joints of the fingers,hip, knee, ankle, and joints of the feet. Examples of diseases ordisorders that may benefit from treatment include osteoarthritis,rheumatoid arthritis, other autoimmune diseases, or osteochondritisdessicans. In addition, cartilage damage or disruption occurs as aresult of certain genetic or metabolic disorders, cartilage malformationis often seen in forms of dwarfism in humans, and/or cartilage damage ordisruption is often a result of reconstructive surgery; thus compounds,compositions, and methods would be useful therapy in these patients,whether alone or in connection with other approaches.

It is further contemplated that compounds, compositions, and methods ofthe present invention may be used to treat, ameliorate or preventvarious cartilagenous disorders and/or associated symptoms or effects ofsuch conditions. Exemplary conditions or disorders for treatment,amelioration and/or prevention with compounds, compositions, and methodsof the invention, include, but are not limited to systemic lupuserythematosis, rheumatoid arthritis, juvenile chronic arthritis,osteoarthritis, degenerative disc disease, spondyloarthropathies, EhlersDanlos syndrome, systemic sclerosis (scleroderma) or tendon disease.Other conditions or disorders that may benefit from treatment withcompounds for amelioration of associated effects include idiopathicinflammatory myopathies (dermatomyositis, polymyositis), Sjogren'ssyndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia(immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmunethrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediatedthrombocytopenia), thyroiditis (Grave's disease, Hashimoto'sthyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis),diabetes mellitus, immune-mediated renal disease (glomerulonephritis,tubulointerstitial nephritis), demyelinating diseases of the central andperipheral nervous systems such as multiple sclerosis, idiopathicdemyelinating polyneuropathy or Guillain-Barr syndrome, and chronicinflammatory demyelinating polyneuropathy, hepatobiliary diseases suchas infectious hepatitis (hepatitis A, B, C, D, E and othernon-hepatotropic viruses), autoimmune chronic active hepatitis, primarybiliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis,inflammatory bowel disease (ulcerative colitis: Crohn's disease),gluten-sensitive enteropathy, and Whipple's disease, autoimmune orimmune-mediated skin diseases including bullous skin diseases, erythemamultiforme and contact dermatitis, psoriasis, allergic diseases such asasthma, allergic rhinitis, atopic dermatitis, food hypersensitivity andurticaria, immunologic diseases of the lung such as eosinophilicpneumonias, idiopathic pulmonary fibrosis and hypersensitivitypneumonitis, transplantation associated diseases including graftrejection and graft-versus-host-disease.

In some embodiments, compounds and compositions of the present inventionare applied by direct injection into the synovial fluid of a joint,systemic administration (oral or intravenously) or directly into acartilage defect, either alone or complexed with a suitable carrier forextended release of protein. In some embodiments, compounds orcompositions are administered in a biocompatible matrix or scaffold.Compounds, compositions, and methods of the present invention can alsobe used in conjunction with a surgical procedure at an affected joint.Administration of a compounds or composition of the invention may occurprior to, during or in conjunction with, and/or after a surgicalprocedure. For example, compounds, compositions and methods of theinvention can be used to expand chondrocyte populations in culture forautologous or allogenic chondrocyte implantation (ACI). Chondrocytes canbe optionally implanted with concurrent treatment consisting ofadministration of compounds and compositions of the present invention.In these procedures, for example, chondrocytes can be harvestedarthroscopically from an uninjured minor load-bearing area of a damagedjoint, and can be cultured in vitro, optionally in the presence ofcompounds and compositions of the present invention and/or other growthfactors to increase the number of cells prior to transplantation.Expanded cultures are then optionally admixed with compounds andcompositions of the present invention and/or placed in the joint spaceor directly into the defect. In certain embodiments, expanded cultures(optionally with compounds of the present invention) are placed in thejoint space suspended in a matrix or membrane. In other embodiments,compounds and compositions of the present invention can be used incombination with one or more periosteal or perichondrial grafts thatcontain cartilage forming cells and/or help to hold the transplantedchondrocytes or chondrocyte precursor cells in place. In someembodiments, compounds and compositions of the present invention areused to repair cartilage damage in conjunction with other procedures,including but not limited to lavage of a joint, stimulation of bonemarrow, abrasion arthroplasty, subchondral drilling, or microfracture ofproximal subchondral bone. Optionally, following administration ofcompounds and compositions of the present invention and growth ofcartilage, additional surgical treatment may be beneficial to suitablycontour newly formed cartilage surface(s).

Collagen is the major structural component of the dermi. Collagen isvital for skin health and has been widely used in dermal treatment ofwrinkles and skin aging, and as a healing aid for burn patients.Collagen is produced in fibroblast, and both human and bovine collagenis widely used. It is contemplated that compounds and/or compositions ofthe present invention can promote expression of collagen in human dermalfibroblast. The invention therefore provides a method of increasingproduction of collagen in fibroblast by contacting the fibroblasts witha compound or composition of the invention, thereby increasing theproduction of collagen in the fibroblast. The contacting may be in vivoby direct injection of the compound in the areas to be treated. Thecontacting may be in vitro into a population of fibroblasts.

A “patient” as used herein refers to any subject that is administered atherapeutic compounds of the invention. It is contemplated that thecompounds, compositions, and methods of the present invention may beused to treat a mammal. As used herein a “subject” refers to any mammal,including humans, domestic and farm animals, and zoo, sports or petanimals, such as cattle (e.g. cows), horses, dogs, sheep, pigs, rabbits,goats, cats, etc. In some embodiments of the invention, the subject is ahuman. In certain embodiments, the subject is a horse. In otherembodiments the subject is a dog.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviate, inhibit,prevent and/or ameliorate a condition, or a disorder or a disease. Inanother non-limiting embodiment, the term “a therapeutically effectiveamount” refers to the amount of the compound of the present inventionthat, when administered to a cell, or a tissue, or a non-cellularbiological material, or a medium, is effective to promotechondrogenesis.

As used herein, the terms “treat”, “treating”, “treatment” plus“ameliorate” and “ameliorating” refer to any indicia of success in thetreatment or amelioration of an injury, pathology, condition, or symptom(e.g., pain), including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the symptom,injury, pathology or condition more tolerable to the patient; decreasingthe frequency or duration of the symptom or condition; or, in somesituations, preventing the onset of the symptom or condition. Thetreatment or amelioration of symptoms can be based on any objective orsubjective parameter; including, e.g., the result of a physicalexamination.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

“At increased risk for” refers to a patient having an above average riskfor a particular disease or condition, wherein the increased risk is aresult of existing health conditions, genetic or family history,existing or prior injuries, repetitive motion actions or conditions.

As used herein, the term “contacting” refers to the process of bringinginto contact at least two distinct species such that they can react. Itshould be appreciated, however, the resulting reaction product can beproduced directly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture.

As used herein, “administering” refers to administration to a specificjoint.

IV. Pharmaceutical Compositions, Medicaments, Kits

Therapeutic compositions comprising compounds of the invention arewithin the scope of the present invention. Thus, in one embodiment, theinvention provides a pharmaceutical composition comprising atherapeutically effective amount of a compound, a salt thereof, or astereoisomer thereof, of the invention, and a pharmaceuticallyacceptable excipient or carrier.

In another embodiment, the invention provides a pharmaceuticalcomposition formulated for intra-articular delivery, the compositioncomprising a pharmaceutically effective amount of a compound, a salt ora stereoisomer thereof, and a pharmaceutically acceptable excipient.

In some embodiment, the pharmaceutical composition can also includeangiopoietin-like 3 protein (ANGPTL3), oral salmon calcitonin, SD-6010(iNOS inhibitor), vitamin D3 (cholecalciferol), collagen hydrolyzate,FGF18, BMP7, avocado soy unsaponifiables (ASU) or hyaluronic acid.ANGPTL3 is described in more detail in WO/2011/008773 (incorporatedherein in its entirety).

In some embodiments, a pharmaceutical composition further comprises ahyaluronic acid or a derivative thereof.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, excipients, disintegrationagents, lubricants, sweetening agents, flavoring agents, dyes, and thelike and combinations thereof, as would be known to those skilled in theart (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, 1990, pp. 1289-1329 and subsequent editions ofthe same). Except insofar as any conventional carrier is incompatiblewith the active ingredient, its use in the therapeutic or pharmaceuticalcompositions is contemplated.

Formulations suitable for administration include excipients, includingbut not limited to, aqueous and non-aqueous solutions, isotonic sterilesolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic, and aqueous andnon-aqueous sterile suspensions that can include suspending agents,solubilizers, thickening agents, stabilizers, and preservatives. Incertain embodiments pharmaceutical compositions comprise atherapeutically effective amount of a compound of the invention inadmixture with a pharmaceutically acceptable formulation agent selectedfor suitability with the mode of administration, delivery format, anddesired dosage. See, e.g., Remington's. The primary vehicle or carrierin a pharmaceutical composition can be aqueous or non-aqueous in nature.For example, a suitable vehicle or carrier for injection can be water,physiological saline solution or artificial cerebrospinal fluid,optionally supplemented with other materials common in compositions forparenteral administration. For example, buffers may be used, e.g., tomaintain the composition at physiological pH or at a slightly lower pH,typically within a range of from about pH 5 to about pH 8, and mayoptionally include sorbitol, serum albumin or other additionalcomponent. In certain embodiments pharmaceutical compositions comprisingcompounds of the invention can be prepared for storage in a lyophilizedform using appropriate excipients (e.g., sucrose).

Suitable solid excipients include, but are not limited to, magnesiumcarbonate; magnesium stearate; talc; pectin; dextrin; starch;tragacanth; a low melting wax; cocoa butter; carbohydrates; sugarsincluding, but not limited to, lactose, sucrose, mannitol, or sorbitol,starch from corn, wheat, rice, potato, or other plants; cellulose suchas methyl cellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins including, but not limited to, gelatin and collagen. Ifdesired, disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For injection,liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for use can be prepared by dissolving theactive component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).The aqueous suspension can also contain one or more preservatives suchas ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

In one embodiment, the compound of the invention may be formulate withan agent, such as injectable microspheres, bio-erodable particles,polymeric compounds, beads, or liposomes or other biocompatible matrixthat provides for controlled or sustained release of the compound of theinvention can then be delivered via a depot injection. For example,compounds of the invention may be encapsulated in liposomes, orformulated as microparticles or microcapsules or may be incorporatedinto other vehicles, such as biodegradable polymers, hydrogels,cyclodextrins (see for example Gonzalez et al., 1999, BioconjugateChem., 10, 1068-1074; Wang et al., International PCT publication Nos. WO03/47518 and WO 03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLCAmicrospheres (see for example U.S. Pat. No. 6,447,796 and US PatentApplication Publication No. US 2002130430), biodegradable nanocapsules,and bioadhesive microspheres, or by proteinaceous vectors (O'Hare andNormand, International PCT Publication No. WO 00/53722) or by the use ofconjugates. Still other suitable delivery mechanisms include implantabledelivery devices.

In another aspect of the present invention, provided compounds orpharmaceutical composition for use as a medicament for treatment ofjoint damage is contemplated. In certain embodiments compounds of theinvention for use as a medicament for amelioration of arthritis or jointdamage are provided. In some embodiments arthritis is osteoarthritis,trauma arthritis or autoimmune arthritis. In some embodiments jointdamage is traumatic joint injury, autoimmune damage, age related damage,or damage related to inactivity.

The medicament, in addition to the compound of the invention, mayfurther include a second agent. The second agent may be one or moreadditional chondrogenic factors (e.g., oral salmon calcitonin, SD-6010(iNOS inhibitor), vitamin D3 (cholecalciferol), collagen hydrolyzate,rusalatide acetate, avocado soy unsaponifiables (ASU), a compounddescribed in WO2012/129562, kartogenin), a steroid, a non-steroidalanti-inflammatory agent (NSAID), etc.). In some embodiment, themedicament may include an agent selected angiopoietin-like 3 protein(ANGPTL3), oral salmon calcitonin, SD-6010 (iNOS inhibitor), vitamin D3(cholecalciferol), collagen hydrolyzate, FGF18, BMP7, rusalatideacetate, avocado soy unsaponifiables (ASU), a steroid, and anon-steroidal anti-inflammatory agent (NSAID) and hyaluronic acid.

Also provided are kits comprising the compound of the invention. In oneembodiment provided are kits for producing a single dose administrationunit. The kit comprises a first container comprising a compound of theinvention as a dried solid and a second container having an aqueousreconstitution formula. In certain embodiments one container comprises asingle chamber pre-filled syringe. In other embodiments the containersare encompassed as a multi-chambered pre-filled syringe.

V. Method of Administration and Dosage

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents.

The compounds and compositions of the present invention can be appliedby direct by direct injection into the synovial fluid of a joint,systemic administration (oral or intravenously) or directly into acartilage defect, either alone or complexed with a suitable carrier forextended release of protein. In some embodiments, compounds orcompositions are administered in a biocompatible matrix or scaffold.Compounds, compositions, and methods of the present invention can alsobe used in conjunction with a surgical procedure at an affected joint.Administration of a compounds of the invention may occur prior to,during or in conjunction with, and/or after a surgical procedure. Forexample, compounds, compositions and methods of the invention can beused to expand chondrocyte populations in culture for autologous orallogenic chondrocyte implantation (ACI). Chondrocytes can be optionallyimplanted with concurrent treatment consisting of administration ofpolypeptides and compositions of the present invention. In theseprocedures, for example, chondrocytes can be harvested arthroscopicallyfrom an uninjured minor load-bearing area of a damaged joint, and can becultured in vitro, optionally in the presence of compounds andcompositions of the present invention and/or other growth factors toincrease the number of cells prior to transplantation. Expanded culturesare then optionally admixed with compounds and compositions of thepresent invention and/or placed in the joint space or directly into thedefect. In certain embodiments, expanded cultures (optionally withcompounds of the present invention) are placed in the joint spacesuspended in a matrix or membrane. In other embodiments, compounds andcompositions of the present invention can be used in combination withone or more periosteal or perichondrial grafts that contain cartilageforming cells and/or help to hold the transplanted chondrocytes orchondrocyte precursor cells in place. In some embodiments, compounds andcompositions of the present invention are used to repair cartilagedamage in conjunction with other procedures, including but not limitedto lavage of a joint, stimulation of bone marrow, abrasion arthroplasty,subchondral drilling, or microfracture of proximal subchondral bone.Optionally, following administration of compound and compositions of thepresent invention and growth of cartilage, additional surgical treatmentmay be beneficial to suitably contour newly formed cartilage surface(s).

Any method for delivering the compound of the invention of the inventionto an affected joint can be used. In the practice of this invention,compositions can be parenterally administered, for example injected,e.g., intra-articularly (i.e., into a joint), intravenously,intramuscularly, subcutaneously; infused, or implanted, e.g., in amembrane, matrix, device, etc. When injected, infused or implanted,delivery can be directed into the suitable tissue or joint, and deliverymay be direct bolus delivery or continuous delivery. In some embodimentsdelivery can be in a suitable tissue located in close proximity to anaffected joint. In some embodiments delivery may be via diffusion, orvia timed release bolus. In some embodiments, a controlled releasesystem (e.g., a pump) can be placed in proximity of the therapeutictarget, e.g., the joint to which the polypeptide is administered. Inother embodiments, compositions can be selected for ingestion, e.g.,inhalation or oral delivery.

The pharmaceutical formulations of the invention can be provided as asalt and can be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thatare the corresponding free base forms. In other cases, the preparationmay be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose,2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with bufferprior to use.

Formulations of compounds can be stored in sterile vials as a solution,suspension, gel, emulsion, solid, or as a dehydrated or lyophilizedpowder. Formulations can be presented in unit-dose or multi-dose sealedcontainers, such as ampules and vials. In some embodiments formulationscan be presented in single or multi-chambered pre-filled syringes (e.g.,liquid syringes, lysosyringes). Solutions and suspensions can beprepared from sterile powders, granules, and tablets of the kindpreviously described.

The dose of a compound of the present invention for treating theabove-mentioned diseases or disorders varies depending upon the mannerof administration, the age and/or the body weight of the subject, andthe condition of the subject to be treated, and ultimately will bedecided by the attending physician or veterinarian. The doseadministered to a subject, in the context of the present inventionshould be sufficient to effect a beneficial response in the subject overtime. Such a dose is a “therapeutically effective amount”. Accordingly,an appropriate dose may be determined by the efficacy of the particularcompound employed and the condition of the subject, as well as the bodyweight or surface area of the area to be treated. The size of the dosealso will be determined by the existence, nature, and extent of anyadverse side-effects that accompany the administration of a particularcompound in a particular subject. Administration can be accomplished viasingle or divided doses, or as a continuous infusion via an implantationdevice or catheter. Frequency of dosing will depend upon thepharmacokinetic parameters of the compound of the invention in theformulation used. A clinician may titer dosage and/or modifyadministration to achieve the desired therapeutic effects.

A typical dosage for intra-articular injection to the knee may rangefrom about 0.1 μM to to about 100 μM, depending on the factors discussedabove.

The compounds and compositions of the invention of the present inventioncan also be used effectively in combination with one or more therapeuticagents.

Non-limiting examples of compounds which can be used in combination withcompounds of the invention includes hyaluronic acid or a derivative orsalt thereof, growth factors (e.g., FGF18, BMP7), chondrogenic agents(e.g., oral salmon calcitonin, SD-6010 (iNOS inhibitor), vitamin D3(cholecalciferol), collagen hydrolyzate, rusalatide acetate, avocado soyunsaponifiables (ASU), other chondrogenesis promoters (e.g., a compounddescribed in WO2012/129562, kartogenin), a steroid, a non-steroidalanti-inflammatory agent (NSAID), etc.). In some embodiments, thecomposition can also include angiopoietin-like 3 protein (ANGPTL3).ANGPTL3 is described in more detail in WO/2011/008773 (incorporatedherein in its entirety). The selection of the second agent would dependon the desired therapy or effect to improve or enhance the therapeuticeffect of either.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of the invention and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

ENUMERATED EMBODIMENTS

Various enumerated embodiments of the invention are described herein. Itwill be recognized that features specified in each embodiment may becombined with other specified features to provide further embodiments ofthe present invention.

In a first embodiment, the invention provides a compound of the formula(I), or a pharmaceutical acceptable salt, tautomer or stereoisomerthereof:

wherein

-   -   “-----” represents a single or double bond;    -   A is CR^(8a)R^(8b), NR⁹, or O; wherein R^(8a), R^(8b) and R⁹ are        each independently hydrogen or C₁₋₆alkyl;    -   L is *—C(O)NR¹⁰— or *—C(O)O—, wherein “*” represents the point        of attachment of L to the bicyclic ring containing A, and R¹⁰ is        hydrogen or C₁₋₆alkyl;    -   R⁰ is selected from hydrogen and C₁₋₆alkyl;    -   R¹ is selected from halo, cyano, —C(O)R¹¹, —C(O)NR^(12a)R^(12b),        —C(O)ONR^(12a)R^(12b), 5- and 6-membered heterocycloalkyl, 5-        and 6-membered heterocyclyl, phenyl, and 5- to 9-membered        heteroaryl, wherein        -   R¹¹ is hydrogen or C₁₋₆alkyl;        -   R^(12a) and R^(12b) are each independently hydrogen or            C₁₋₆alkyl;        -   the heterocycloalkyl, heterocyclyl, phenyl, or heteroaryl of            R¹ is unsubstituted or substituted by 1 to 2 substituents            independently selected from halo, cyano, C₁₋₆alkyl,            C₁₋₆haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b), 5- and            6-membered heterocycloalkyl, phenyl, and 5- and 6-membered            heteroaryl; wherein            -   R¹³ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,                amino, and C₁₋₆alkylamino;            -   R^(14a) and R^(14b) are each independently selected from                hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, —C(O)OR¹⁵, and —S(O)₂R¹⁵,                wherein R¹⁵ is hydrogen or C₁₋₆alkyl; and            -   the heterocycloalkyl, phenyl or heteroaryl substituent                of R¹ is further substituted by 1 to 2 substituents                independently selected from halo, C₁₋₆alkyl,                C₁₋₆haloalkyl, and hydroxy;    -   R³ is selected from C₁₋₆alkyl, C₁₋₆haloalkyl, 3- to 6-membered        cycloalkyl, (159), 4- to 7-membered heterocycloalkyl, 5- to        10-membered heterocyclyl, phenyl, and 5- to 9-membered        heteroaryl, wherein        -   the cycloalkyl, heterocycloalkyl, heterocyclyl, phenyl, or            heteroaryl of R³ is unsubstituted or substituted by 1 to 2            substituents independently selected from halo, cyano,            C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,            —C(O)R¹⁶, —C(O)OR¹⁶, —S(O)₂R¹⁶, 5 and 6 membered            heterocycloalkyl, and phenyl; wherein            -   R¹⁶ is hydrogen or C₁₋₆alkyl;            -   the phenyl or heterocycloalkyl substituent or R³ is                unsubstituted or further substituted by 1 to 2                substituents independently selected from halo, cyano,                C₁₋₆alkyl, and C₁₋₆haloalkyl; and    -   R² and R⁴ are each hydrogen or C₁₋₆alkyl; or R² and R⁴ taken        together form a cyclopropyl ring fused to the bicyclic ring        containing A; or R² and R⁴ taken together form a bond producing        a double bond between the two carbons to which R² and R⁴ are        attached; and    -   R⁵ is hydrogen or C₁₋₆alkyl, or R⁵ and R¹⁰ taken with the atoms        to which they are linked form a 5- or 6-membered ring fused to        the bicyclic ring containing A; and    -   R⁶ and R⁷ are each hydrogen or C₁₋₆alkyl; or R⁶ and R⁷ taken        together form a bond producing a double bond between the two        carbons to which R⁶ and R⁷ are attached.

Embodiment 2. A compound according to Embodiment 1 or salt, tautomer orstereoisomer thereof, wherein the compound is of Formula IA:

-   -   “-----” represents a single or double bond;    -   R⁰ is selected from hydrogen and C₁₋₆alkyl;    -   R¹ is selected from cyano, —C(O)NR^(12a)R^(12b), 6-membered        heterocycloalkyl, 6-membered heterocyclyl, phenyl, and 5- to        9-membered heteroaryl, wherein        -   R^(12a) and R^(12b) are each independently hydrogen or            C₁₋₆alkyl;        -   the heterocycloalkyl, heterocyclyl, phenyl, or heteroaryl of            R¹ is unsubstituted or substituted by 1 to 2 substituents            independently selected from halo, cyano, C₁₋₆alkyl,            C₁₋₆haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b), 5- and            6-membered heterocycloalkyl, phenyl, and 5- and 6-membered            heteroaryl; wherein            -   R¹³ is selected from C₁₋₆alkyl, amino, and                C₁₋₆alkylamino;            -   R^(14a) and R^(14b) are each independently selected from                hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, —C(O)OR¹⁵, and —S(O)₂R¹⁵,                wherein R¹⁵ is hydrogen or C₁₋₆alkyl; and            -   the heterocycloalkyl, phenyl or heteroaryl substituent                of R¹ is unsubstituted or further substituted by 1 to 2                substituents independently selected from halo, hydroxy,                C₁₋₆alkyl, and C₁₋₆haloalkyl,    -   R³ is selected from C₁₋₆alkyl, C₁₋₆haloalkyl, 5- and 6-membered        cycloalkyl, (159), 5- and 6-membered heterocycloalkyl, 6- and        10-membered heterocyclyl, phenyl, and 5- and 6-membered        heteroaryl, wherein        -   the cycloalkyl, heterocycloalkyl, heterocyclyl, phenyl, or            heteroaryl of R³ is unsubstituted or substituted by 1 to 2            substituents independently selected from halo, cyano,            C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,            —C(O)R¹⁶, —C(O)OR¹⁶, —S(O)₂R¹⁶, 5- and 6-membered            heterocycloalkyl, and phenyl; wherein            -   R¹⁶ is hydrogen or C₁₋₆alkyl;            -   the phenyl or heterocycloalkyl substituent of R³ is                unsubstituted or further substituted by 1 to 2                substituents independently selected from halo, and                cyano; and    -   R² and R⁴ are each hydrogen or C₁₋₆alkyl; or R² and R⁴ taken        together form a cyclopropyl ring fused to the bicyclic ring; or        R² and R⁴ taken together form a bond producing a double bond        between the two carbons to which R² and R⁴ are attached; and    -   R⁵ is hydrogen or C₁₋₆alkyl, or R⁵ and R¹⁰ taken with the atoms        to which they are linked form a 5- or 6-membered ring fused to        the bicyclic ring, and    -   R⁶ and R⁷ are each hydrogen or C₁₋₆alkyl; or R⁶ and R⁷ taken        together form a bond producing a double bond between the two        carbons to which R⁶ and R⁷ are attached.

Embodiment 3. A compound according to Embodiment 1 or 2, or salt,tautomer or stereoisomer thereof, wherein the compound is of a formulaselected from:

Embodiment 4. A compound according to any one of Embodiments 1 to 3, orsalt, tautomer or stereoisomer thereof, wherein R¹ is phenyl, 5- or6-membered heteroaryl, wherein the phenyl or heteroaryl is unsubstitutedor substituted by 1 to 2 substituents independently selected from halo,cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b),5- and 6-membered heterocycloalkyl, phenyl, and 5- and 6-memberedheteroaryl, wherein

-   -   R¹³ is selected from C₁₋₆alkyl, amino, and C₁₋₆alkylamino;    -   R^(14a) and R^(14b) are each independently selected from        hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, and —C(O)OR¹⁵, wherein R¹⁵ is        C₁₋₆alkyl; and    -   the heterocycloalkyl, phenyl or heteroaryl substituent of R¹ is        unsubstituted or further substituted by 1 to 2 substituents        independently selected from hydroxy, halo, C₁₋₆alkyl, and        C₁₋₆haloalkyl.    -   R¹³ is selected from C₁₋₆alkyl, amino, and C₁₋₆alkylamino;    -   R^(14a) and R^(14b) are each independently selected from        hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, and —C(O)OR¹⁵, wherein R¹⁵ is        C₁₋₆alkyl; and    -   the heterocycloalkyl or phenyl substituent of R¹ is        unsubstituted or further substituted by 1 to 2 substituents        independently selected from hydroxy, halo, C₁₋₆alkyl, and        C₁₋₆haloalkyl.

Embodiment 5. A compound according to any one of Embodiments 1 to 3, orsalt, tautomer or stereoisomer thereof, wherein R¹ is selected from

wherein “*” represents the point of attachment of R¹ to the bicycliccore ring.

Embodiment 6. A compound according to any one of Embodiments 1 to 5, orsalt, tautomer or stereoisomer thereof, wherein R³ is phenyl, 5- or6-membered heteroaryl, wherein

-   -   the phenyl, or heteroaryl of R³ is unsubstituted or substituted        by 1 to 2 substituents independently selected from halo, cyano,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —C(O)R¹⁶,        —C(O)OR¹⁶, —S(O)₂R¹⁶, 5- and 6-membered heterocycloalkyl, and        phenyl; wherein        -   R¹⁶ is C₁₋₆alkyl; and        -   the phenyl or heterocycloalkyl substituent or R³ is            unsubstituted or further substituted by 1 to 2 substituents            independently selected from halo or cyano.

Embodiment 7. A compound according to any one of Embodiments 1 to 5, orsalt, tautomer or stereoisomer thereof, wherein R³ is selected from:

wherein “*” represents the point of attachment of R³ to the bicyclicring.

Embodiment 8. A compound according to Embodiment 1, or salt, tautomer orstereoisomer thereof, wherein the compound is of Formula 1B:

or a pharmaceutically acceptable salt, or a stereoisomer thereof,wherein

-   -   “-----” represents a single or double bond;    -   R¹ is phenyl, 5- or 6-membered heteroaryl, wherein        -   the phenyl or heteroaryl of R¹ is unsubstituted or            substituted by 1 to 2 substituents independently selected            from halo, cyano, C₁₋₆alkyl, C₁₋₄haloalkyl, —C(O)R¹³,            —C(O)OR¹³, —NR^(14a)R^(14b), 5- and 6-membered            heterocycloalkyl, phenyl, and 5- and 6-membered heteroaryl,            wherein            -   R¹³ is C₁₋₆alkyl or amino;            -   R^(14a) and R^(14b) are independently is selected from                hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, and —C(O)OR¹⁵, wherein                R¹⁵ is C₁₋₄alkyl; and            -   the heterocycloalkyl, phenyl, or heteroaryl substituent                of R¹ is unsubstituted or substituted by 1 to 2                substituents independently selected from halo, hydroxy,                and C₁₋₆alkyl;    -   R³ is phenyl, 5- or 6-membered heteroaryl, wherein the phenyl or        heteroaryl is unsubstituted or substituted by 1 to 2        substituents independently selected from halo, cyano, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —C(O)R¹⁶, —C(O)OR¹⁶,        5- and 6-membered heterocycloalkyl, and phenyl, wherein        -   R¹⁶ is C₁₋₆alkyl; and        -   the heterocycloalkyl or phenyl is unsubstituted or            substituted by 1 to 2 substituents selected from halo and            cyano;    -   R² and R⁴ are independently hydrogen or C₁₋₆alkyl, or R² and R⁴        taken together form a cyclopropyl fused to the bicyclic ring, or        R² and R⁴ taken together form a bond, producing a double bond        between the two carbons to which R² and R⁴ are attached.

Embodiment 9. A compound according to Embodiment 8, or salt, tautomer orstereoisomer thereof, wherein the compound is of a formula selected from

Embodiment 10. A compound according to Embodiment 8 or 9, or salt,tautomer or stereoisomer thereof, wherein the compound is of a formulaselected from the formulae:

Embodiment 11. A compound according to any one of Embodiments 8 to 10,or salt, tautomer or stereoisomer thereof, wherein R1 is a 5 or 6membered heteroaryl, unsubstituted or substituted by 1 to 2 substituentsindependently selected from halo, C1-4alkyl, C1-4haloalkyl, and NHR14b,wherein R14b is hydrogen or C1-4alkyl.

Embodiment 12. A compound according to any one of Embodiments 8 to 10,or salt, tautomer or stereoisomer thereof, wherein R1 is selected frompyrazolyl, oxadiazolyl, pyridinyl, pyrimidinyl and pyrazinyl, whereinthe pyrazolyl, pyridinyl, pyrimidinyl or pyrazinyl is unsubstituted orsubstituted by —NH2, —NHC(O)OCH3 or trifluoromethyl.

Embodiment 13. A compound according to any one of Embodiments 8 to 10,or salt, tautomer or stereoisomer thereof, wherein R1 is selected from:

wherein “*” represents the point of attachment of R1 to the bicycliccore ring.

Embodiment 14. A compound according to any one of Embodiments 8 to 13,or salt, tautomer or stereoisomer thereof, wherein R3 is phenylsubstituted by 1 to 2 substituents independently selected from halo,cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, and phenyl,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —C(O)R¹⁶,—C(O)OR¹⁶, wherein R¹⁶ is C₁₋₆alkyl, and the phenyl substituent of R³ isunsubstituted or further substituted by 1 to 2 substituentsindependently selected from halo and cyano.

Embodiment 15. A compound according to any one of Embodiments 8 to 13,or salt, tautomer or stereoisomer thereof, wherein R³ is selected from:

wherein “*” represents the point of attachment of R¹ to the bicycliccore ring.

Embodiment 16. A compound according to Embodiment 1 or salt, tautomer orstereoisomer thereof, wherein the compound is selected from the list ofcompounds set forth in Table 3 and listed on pages 31 to 38 of thespecification.

Embodiment 17. A pharmaceutical composition comprising a compoundaccording to any one of Embodiments 1 to 16, or a salt or a stereoisomerthereof, and a pharmaceutically acceptable excipient.

Embodiment 18. A pharmaceutical composition formulated forintra-articular delivery, the composition comprising a pharmaceuticallyeffective amount of a compound, according to any one of Embodiments 1 to16, or a salt or a stereoisomer thereof, and a pharmaceuticallyacceptable excipient.

Embodiment 19. A pharmaceutical composition according to Embodiment 17or 18, composition comprising an agent selected from angiopoietin-like 3protein (ANGPTL3), oral salmon calcitonin, SD-6010 (iNOS inhibitor),vitamin D3 (cholecalciferol), collagen hydrolyzate, FGF18, BMP7,rusalatide acetate, avocado soy unsaponifiables (ASU), a steroid, and anon-steroidal anti-inflammatory agent (NSAID) and hyaluronic acid.

Embodiment 20. A method of treating, ameliorating or preventingarthritis or joint injury in a mammal in need thereof, the methodcomprising administering to a joint of the mammal a therapeuticallyeffective amount of a compound according to any one of Embodiments 1 to16, or a pharmaceutical composition according to any one of Embodiments16 to 18, thereby treating, ameliorating or preventing arthritis orjoint damage in the mammal.

Embodiment 21. A method of treating, ameliorating or preventingarthritis or joint injury in a mammal in need thereof, according toEmbodiment 20, wherein the arthritis is osteoarthritis, traumaarthritis, or autoimmune arthritis.

Embodiment 22. A method of treating, ameliorating or preventingarthritis or joint injury according to Embodiment 20 or 21, whereinadministering the compound or pharmaceutical composition occurs in amatrix or biocompatible scaffold.

Embodiment 23. A method of inducing differentiation of mesenchymal stemcells into chondrocytes, wherein the method comprising contactingmesenchymal stem cells with a sufficient amount of a compound, accordingto any one of Embodiments 1 to 16, or a salt or a stereoisomer thereof,or a pharmaceutical composition according to any one of Embodiments 17to 19, thereby inducing differentiation of the stem cells intochondrocytes.

Embodiment 24. A method of inducing differentiation of mesenchymal stemcells into chondrocytes according to Embodiment 23, wherein thecontacting is performed in vitro or in vivo in a mammal, and when invivo, the stem cells are present in the mammal.

Embodiment 25. A method of inducing differentiation of mesenchymal stemcells into chondrocytes according to Embodiment 23 or 24, wherein thecontacting compound occurs in a matrix or biocompatible scaffold.

Embodiment 26. A method of inducing differentiation of mesenchymal stemcells into chondrocytes according to any one of Embodiments 23 to 25,wherein contacting the compound occurs in conjunction with one or moreadditional chondrogenic factors.

Embodiment 27. A method of inducing differentiation of mesenchymal stemcells into chondrocytes according to any one of Embodiments 23 to 25,wherein contacting the compound occurs in conjunction with an agentselected from angiopoietin-like 3 protein (ANGPTL3), oral salmoncalcitonin, SD-6010 (iNOS inhibitor), vitamin D3 (cholecalciferol),collagen hydrolyzate, FGF18, BMP7, rusalatide acetate, avocado soyunsaponifiables (ASU), a steroid, and a non-steroidal anti-inflammatoryagent (NSAID) and hyaluronic acid.

Biological Assays

The compounds of the present invention were evaluated in two functionalassays to assess their chondrogenesis activities (Type II CollagenExpression) and chondrocyte protective activities (NO release assay).

Type II Collagen Expression Assay

Cell-based 2D chondrogenesis was induced in vitro and assessed asdescribed previously in Johnson, K., et al., (2012) Science 336, 717.The assay measures type II collagen, a chondrocytes specific protein.Briefly, primary human bone marrow derived mesenchymal stem cells(hMSCs) were plated in growth media then subsequently changed to achondrogenic stimulation media with and without constructs, and culturedfor 7 or 14 days. Cells were then fixed with formaldehyde, washed andthen stained using standard immuno-cytochemical techniques to detectType II collagen. a primary cartilage proteins.

Cell Culture and Differentiation

Primary human bone marrow derived mesenchymal stem cells (hMSCs) werepurchased from Lonza (Walkersville, Md.). The cells were FACS sorted andproven to be >98% positive for CD29, CD44, CD166 and CD105 and <0.1%positive for CD45. The hMSCs were grown in Mesenchymal Stem Cell GrowthMedium (MSCGM) (Lonza, Walkersville, Md.) and used from passages 2-8 forall of the experiments. Human cartilage resident MSCs (hCR-MSCs) werederived from human primary articular chondrocytes (Lonza, Walkersville,Md.) which were separated into single cells, clonally grown in MSCGM andvalidated as MSCs through chondrogenic, osteogenic and adipogenicdifferentiation. The cells were FACS sorted and proven to be >98%positive for CD166 and CD105. hCR-MSCs were cultured up to 20 passageswith no alteration in the cell profile, growth or differentiation ratesidentified.

To initiate chondrogenesis in primary hMSCs or CR-MSCs, 5000 cells wereplated/well in a Griener 384 well plate in MSCGM. After 24 hours theMSCGM was removed and replaced with 25 μl of DMEM containing 1% FBS. Thetest compound was then added to each well at the indicated dose. Thecultures were grown at 37° C. for 18 days. A media supplement of anadditional 25 μl of DMEM containing 1% FBS was given 10 days afterchondrogenic induction.

Immunocytochemical Staining and Quantitation

To detect the presence of chondrogenic proteins, cells were fixed with10% formalin for 15 minutes, permeabalized with PBS containing 0.1%triton X-100, 0.25 g/ml of Collagenase 2 for 10 minutes, blocked withPBS containing 5% BSA for 1 hr at room temperature, followed byincubation with primary antibody (anti-type II collagen antibody) in PBScontaining 1% BSA overnight at 4° C. Cells were washed 3 times with PBSand incubated with fluorophore-conjugated secondary antibody and DAPI orTO-PRO3 for 1 hour at room temperature, followed by washing with PBS for3 times.

The total intensity of staining was imaged by fluorescent microscopyand/or quantified by high content imagining with the ImageXpress Ultra(Molecular Devices, Sunnyvale, Calif.). Data analyses were performedwith the customized multiwavelength cell-scoring application. The resultis reported as the maximum efficacy observed at 40 μM concentration ofthe test compound in Table 2 below.

Reagents

TABLE 1 Reagents used for experimentation Dilution/ Description CompanyCatalog number Concentration Anti-type II collagen Abcam 3092 1:500Anti-mouse 488 Life Technologies A-11099 1:1000 Anti-Rabbit 594 LifeTechnologies A-11005 1:1000 Anti-aggrecan Millipore AB1031 1:500Anti-Sox9 Abcam AB26414 1:250 TO-PRO3 Life Technologies T-3065 1:1000DAPI Sigma D8417 2 μg/ml Anti-Type X collagen Abcam Ab58632 1:1000

NO Release Assay in Bovine Chondrocytes

The assay was described in Johnson, K., et al., (2012) Science 336,717-721. Chondrocytes release NO during OA pathogenesis. This assaymeasures the inhibition of nitric oxide release by the treated compound(an indicator of chondro-protection)

Primary articular chondrocytes from normal bovine knees (AnimalTechnologies, Tyler, Tex.) were isolated after dissection andcollagenase digestion (Worthington Biochemical) of the tibial plateauand femoral condyle articular cartilage. The cells were initially platedat 80-90% confluency after isolation. Primary chondrocytes were culturedin high-glucose Dulbecco's modified Eagle's medium (DMEM) supplementedwith 10% fetal bovine serum (FBS), 1% L-glutamine, 100 units/ml ofpenicillin, and 50 μg/ml of streptomycin (Life Technologies, Carlsbad,Calif.) and maintained at 37° C. in the presence of 5% CO2 for 7 daysprior to initiation of each experiment. During the 7-day culture period,the cells adhered and established a chondrocyte-like appearance that wasmaintained throughout the experimental period. Functional studies onchondrocytes were performed in high-glucose DMEM with no FBS unlessindicated otherwise.

After one week of culture, 8500 cells were plated per well in Greiner384 well white clear bottom plates in growth media. Following 24 hoursof culture, the media was removed and replaced with serum free DMEMcontaining 20 ng/ml TNFα and 10 ng/ml human oncostatin M (inflammatorymediators). The cells were treated for 48 hours with and without thetest compound (where indicated) to assess the inhibition of the cytokineinduced-NO release. 20 μl of the supernatant was mixed with 20 μl of theGreiss reagent (Promega #G2930) and quantitated at 540 nm. The Greissreagent part A (1% Sulfanilamide in 5% phosphoric acid) was mixed at a1:1 ration with Greiss reagent part B (0.1% N-1-naphtylethylenediaminedihydrochloride in water) immediately prior to added to the culturesupernatant. The μM concentration of the test compound at IC50 isreported in Table 2 below.

TABLE 2 Activity of the Compounds of the Invention in InducingChondrogenesis and in Inhibiting NO Release Collagen Type II Max Eff Ex.observed NO Inh. No. μM (Eff) IC₅₀ (μM)   1 40 (102) ND   2 40(1372) >30   3 40 (188) ND   4 40 (234) ND   5 40 (2759) 16   6 40 (304)ND   7 40 (350) ND   8 40 (367) >33   9 40 (3901) >11.1  10 40 (393) 22 11 40 (435) >33  12 40 (443) ND  13 40 (65) ND  14 40 (8224) ND  15 40(853) ND  16 40 (90) ND  17 40 (955) >11.1  18 40 (109) >33  19 40(1147) ND  20 40 (1160) >33  21 40 (1329) ND  22 40 (1378) ND  23 40(1447) ND  24 40 (155) >33  25 40 (157) ND  26 40 (1660) >3.4  27 40(1676) >33  28 40 (172) ND  29 40 (1890) ND  30 40 (191) ND  31 40(199) >33  32 40 (2165) >27  33 40 (235) >33  34 40 (254) ND  35 40(3145) ND  36 40 (334) ND  37 40 (347) ND  38 40 (357) >33  39 40(3601) >33  40 40 (36305) ND  41 40 (371) >33  42 40 (392) ND  43 40(4523) >33  44 40 (4578) 28  45 40 (460) ND  46 40 (4960) ND  47 40(5160) 18  48 40 (5231) ND  49 40 (5500) >33  50 40 (565) 14  51 40 (58)26  52 40 (612) >33  53 40 (623) ND  54 40 (63) >33  55 40 (64) ND  5640 (6656) >33  57 40 (6833) ND  58 40 (69) ND  59 40 (700) ND  60 40(71) ND  61 40 (74) >33  62 40 (76) 15  63 40 (814) ND  64 40 (8429) >33 65 40 (88) >33  66 40 (883) ND  67 40 (94) >33  68 40 (943) ND  69 40(953) 21  70 40 (954) >33  71 40 (1286) >29  72 20 (102) ND  73 40(1035) ND  74 40 (107) >33  75 40 (117) ND  76 40 (1194) >33  77 40(125) ND  78 40 (135) 0.24  79 40 (139) ND  80 40 (145) >17  81 40 (149)ND  82 40 (1546) ND  83 40 (1610) >33  84 40 (1637) ND  85 40 (1669) ND 86 40 (1673) >33  87 40 (1750) >33  88 40 (1800) ND  89 40 (2087) >33 90 40 (2440) ND  91 40 (2555) ND  92 40 (2603) >33  93 40 (268) >33  9440 (2741) ND  95 40 (2907) 0.18  96 40 (3222) ND  97 40 (3620) 22.6  9840 (3645) >33  99 40 (3747) ND 100 40 (458) ND 101 40 (51) ND 102 40(52) ND 103 40 (546) >29 104 40 (56) >33 105 40 (57) ND 106 40 (571) ND107 40 (5766) >33 108 40 (589) ND 109 40 (66) >33 110 40 (681) ND 111 40(708) >33 112 40 (709) ND 113 40 (72) ND 114 40 (7238) ND 115 40 (74) 26116 40 (750) 0.12 117 40 (810) ND 118 40 (825) >33 119 40 (86) ND 120 40(86) ND 121 40 (105) >23 122 40 (186) >33 123 40 (918) >11 124 40 (104)ND 125 40 (111) ND 126 40 (119) ND 127 40 (1269) ND 128 40 (134) ND 12940 (1377) >33 130 40 (153) ND 131 40 (170) ND 132 40 (172) ND 133 40(1765) ND 134 40 (189) ND 135 40 (191) >33 136 40 (1937) 0.14 137 40(1987) 8.2 138 40 (205) ND 139 40 (227) ND 140 40 (238) >33 141 40(2508) 17 142 40 (268) >33 143 40 (2703) ND 144 40 (288) >33 145 40(291) ND 146 40 (295) ND 147 40 (315) ND 148 40 (324) ND 149 40 (336) ND150 40 (34502) ND 151 40 (3753) >33 152 40 (4144) ND 153 40 (444) ND 15440 (445) ND 155 40 (4599) >33 156 40 (4730) ND 157 40 (4735) 25 158 40(481) ND 159 40 (485) ND 160 40 (5050) 5.4 161 40 (513) ND 162 40(549) >33 163 40 (55) ND 164 40 (60) >33 165 40 (6280) ND 166 40(631) >33 167 40 (644) >33 168 40 (67) ND 169 40 (695) ND 170 40 (73) ND171 40 (77) ND 172 40 (824) ND 173 40 (849) ND 174 40 (904) ND 175 40(96) ND 176 40 (55) ND ND means no data

EXAMPLES

The present invention is further exemplified, but not to be limited, bythe following examples and intermediates that illustrate the preparationof compounds of Formula I according to the invention. It is understoodthat if there appears to be a discrepancy between the name and structureof a particular compound, the structure is to be considered correct asthe compound names were generated from the structures.

Temperatures are given in degrees Celsius. If not mentioned otherwise,all evaporations are performed under reduced pressure, typically betweenabout 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis and spectroscopiccharacteristics, e.g., MS, IR, NMR. Abbreviations used are thoseconventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

LC-MS Method

Method A: (2.0 min) (C18, 10-100% ACN (0.035% TFA) in water (0.05% TFA)over 2 min).

Example 1: Synthesis of(1R,2R,3S,4S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Compound 107) and(1R,2S,3S,4S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Compound 115) Step 1: Preparation of methyl3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate, (IntermediateI-1)

A solution of ethyl propiolate (2.03 mL, 20.0 mmoL) in acetone (40 mL)at RT was treated with silver nitrate (340 mg, 2.00 mmol). After 5minutes, NBS (3.92 g, 22.0 mmol) was added and the reaction was stirredat RT for 3 hours. The reaction mixture was filtered through a pad ofcelite, which was washed with acetone (3×20 mL). Concentration of theacetone solution provided crude brominated alkyne, which was useddirectly in the next step without purification. (Note: the alkyne isvolatile and must not be placed on a high vac line).

A solution of alkyne (50.8 mmol) in furan (22 mL, 305 mmol) wastransferred into 4-40 mL thick vials with caps. The reaction vials werewarmed at 80° C. for 20 h. The reaction was cooled to RT and the solventremoved under reduced pressure. The crude compound was taken up in DCMand purified by FCC (hexanes/ethyl acetate) to afford the desiredproduct Intermediate I-1 (8.1 g, 65%). LCMS m/z (M+1, 245, 247). Thiscompound is known in the art and has been described in the literature.

An alternate procedure for the bromination using methyl propiolate isdescribed in a 2003 US patent publication US2003/236270 A1. Methylpropiolate (52 ml, 0.583 mol) is combined with recrystallizedN-bromo-succinimide (120 g, 0.674 mol) in 1,700 ml acetone undernitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583mol) neat in a single lot and the reaction is stirred 6 h at RT. Theacetone is removed under reduced pressure (25° C., bath temperature) toprovide a gray slurry. The slurry is washed with 2×200 ml hexane, thegray solid is removed by filtration, and the filtrate is concentrated invacuo to provide 95 g of a pale yellow oily residue. The crude materialwas distilled via short path under reduced pressure (65° C., about 25 mmHg) into a dry ice/acetone cooled receiver to give 83.7 g (88%) ofmethyl-3-bromo-propiolate as a pale yellow oil.

ADDITIONAL LITERATURE

-   1. Poulsen, Thomas B.; Bernardi, Luca; Aleman, Jose; Overgaard,    Jacob; Joergensen, Karl Anker Journal of the American Chemical    Society 2007, 129, 441-449.-   2. Andersen, Neil G.; Maddaford, Shawn P.; Keay, Brian A. Journal of    Organic Chemistry 1996, 61, 2885-2887.-   3. Leroy, Jacques Tetrahedron Letters 1992, 33, 2969-2972.-   4. Christensen, Helena S.; Boye, Soeren V.; Thinggaard, Jacob:    Sinning, Steffen; Wiborg, Ove; Schioett, Birgit; Bols, Mikael    Bioorganic and Medicinal Chemistry 2007, 15, 5262-5274.-   5. Rainier, Jon D.; Xu, Qing Organic Letters 1999, 1, 27-29.

Step 2. Preparation of methyl3-bromo-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (Intermediate I-2)

To a stirring solution of I-1 (5 g, 20.40 mmol) in EtOAc (50 mL) wasadded 10% palladium on carbon (2.5 g, wet basis). The reaction mixturewas hydrogenated at 1 atm for 3 h. LCMS showed the reaction to becomplete. The reaction was filtered over celite and washed with EtOAc.The solvent was concentrated and the crude compound was purified by FCC(hexanes/EtOAc) to afford the desired product Intermediate I-2 (3.2 g,56%). LCMS m/z (M+1, 247, 249); ¹H NMR (400 MHz, DMSO) δ 5.18 (d, J=4.0Hz, 1H), 5.07 (d, J=4.0 Hz, 1H), 4.21-4.13 (M, 2H), 1.85-1.75 (m, 2H),1.38-1.32 (m, 2H), 1.24 (t, J=8.0 Hz, 3H). This compound is known in theart and has been described in the literature.

LITERATURE

-   1. Christensen, Helena S.; Boye, Soeren V.; Thinggaard, Jacob;    Sinning, Steffen; Wiborg, Ove; Schioett, Birgit; Bols, Mikael    Bioorganic and Medicinal Chemistry 2007, 15, 5262-5274.-   2. Bull. Korean Chem. Soc. 2007, 28, 307.

Step 3. Preparation of tert-butyl3-bromo-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (Intermediate I-3)

A solution of I-2 (4.00 g, 17.2 mmol) in 2:1:1 THF:MeOH:water (100 mL)was treated with LiOH (1.23 g, 51.5 mmol) and stirred at RT for 2 hours.LCMS showed the reaction to be complete. The reaction was quenched withsat. aq. NH₄Cl, diluted with EtOAc, washed with water and brine, dried(Na₂SO₄), and concentrated. The resulting oil (3.33 g, 15.2 mmol) wasdissolved in toluene (20 mL) was treated with DMF di-t-butyl acetal(18.2 mL, 76.0 mmol) and stirred at 60° C. for 16 hours. LCMS showedformation of a new product. The solvent was removed under reducedpressure and the resulting oil was purified by FCC (EtOAc/hexanes) toafford Intermediate I-3 (2.07 g, 47%). LCMS m/z (M+H-tBu, 219.0, 221.0);¹H NMR (400 MHz, DMSO) δ 5.16-5.09 (m, 1H), 5.06-4.99 (m, 1H), 1.85-1.73(m, 2H), 1.46 (s, 9H), 1.38-1.27 (m, 2H).

Step 4. Preparation of tert-butyl7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (Intermediate I-4)

To a stirring solution of I-3 (10 g, 36.3 mmol) in THF (24 mL) and water(24 mL) at 0° C. was added acetic acid (10.4 mL) and portion-wise Znpowder (7.1 g, 109 mmol). The reaction slurry was stirred to roomtemperature for 30 minutes. Additional Zn powder (˜10 g) was added asneeded to get the reaction to go to completion. The reaction wasfiltered through a plug of celite and the solid was washed with EtOAc.The filtrate was neutralized with saturated sodium bicarbonate (pH˜8-10), further diluted with EtOAc, washed with water and brine, dried(Na₂SO₄), filtered, and concentrated. The resulting yellow oil,Intermediate I-4, (7.0 grams, 98%) was used in the next step withoutfurther purification. LCMS m/z (M+H-tBu, 141.1); ¹H NMR (400 MHz, CDCl₃)δ 6.90 (d, J=1.8 Hz, 1H), 5.19-5.15 (m, 1H), 5.08-5.06 (m, 1H),1.94-1.81 (m, 2H), 1.49 (s, 9H), 1.33-1.25 (m, 2H).

Step 5. Preparation ofN-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide(Intermediate I-5)

To a stirring solution of I-4 (3.50 g, 17.8 mmol) in 1,4-dioxane (6 mL)was added HCl (37%, 6 mL). The reaction was stirred at room temperaturefor 2 h. LCMS showed the reaction was complete. The solvent was removedunder reduced pressure and the compound was diluted with water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried (Na₂SO₄), filtered, and concentrated. The crudecarboxylic acid product (2.4 g) was dissolved in anhydrous pyridine (12mL) with 3,4-dichloroaniline (2.30 g, 14.3 mmol), EDCI (4.00 g, 21.4mmol) and DMAP (872 mg, 7.14 mmol). The reaction was stirred at roomtemperature for 4 h. The solvent was removed under reduced pressure andthe resulting residue was taken up in ethyl acetate and 1M HCl. Theorganic layer was washed with 1M HCl and brine, dried (Na₂SO₄),filtered, and concentrated. The resulting residue was purified by FCC toafford Intermediate I-5 as a tan solid (1.5 g, 30% overall). LCMS m/z(M+H, 283.1); ¹H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.04 (d, J=2.3 Hz,1H), 7.63 (dd, J=8.9, 2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.10 (d,J=1.8 Hz, 1H), 5.22 (d, J=4.0 Hz, 1H), 5.18-5.15 (m, 1H), 1.80-1.74 (m,2H), 1.28-1.20 (m, 2H).

Step 6. Preparation of Compound 107 and Compound 115

A mixture I-5 (500 mg, 1.76 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (581 mg,2.64 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthalene (110 mg, 0.176mmol), chloro(1,5-cyclooctadiene)rhodium(I) dimer (43 mg, 0.088 mol) andpotassium carbonate (121 mg, 0.88 mmol) in dioxane (10 mL) and water (2mL) was heated in the microwave at 100° C. for 1 h. LCMS shows two peakswith mass M+1, 378, 380; one minor and major. The crude reaction wasfiltered and the crude compound was purified by HPLC (10 to 70% 0.05%TFA in acetonitrile). The fractions containing the second peak to elutewere concentrated under reduced pressure. The resulting residue wastaken up in ethyl acetate, washed with 10% aq. sodium bicarbonate, waterand brine, dried (Na₂SO₄), filtered, and concentrated. The resultingresidue was taken up in 1:1 water/acetonitrile and was lyophilized toafford Compound 107 (324 mg, 46%) as a white solid. The same was processwas performed for the first peak to elute off the HPLC to affordCompound 115 (95 mg, 14%).

Compound 107: LCMS m/z (M+H, 378.1); ¹H NMR (400 MHz, DMSO) δ 10.34 (s,1H), 8.01 (d, J=2.4 Hz, 1H), 7.79 (d, J=5.2 Hz, 1H), 7.57 (d, J=9.0 Hz,1H), 7.44 (dd, J=8.9, 2.4 Hz, 1H), 6.39 (dd, J=5.2, 1.5 Hz, 1H), 6.33(d, J=1.4 Hz, 1H), 5.85 (s, 2H), 4.86 (t, J=5.1 Hz, 1H), 4.54 (d, J=4.6Hz, 1H), 3.17 (d, J=5.1 Hz, 1H), 2.99 (td, J=5.2, 1.5 Hz, 1H), 1.78-1.46(m, 4H).

Compound 115 LCMS m/z (M+H, 378.0); ¹H NMR (400 MHz, DMSO) δ 9.51 (s,1H), 7.50 (d, J=5.3 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.32 (d, J=8.8 Hz,1H), 7.00 (dd, J=8.8, 2.4 Hz, 1H), 6.32 (d, J=5.5 Hz, 2H), 5.56 (s, 2H),4.78 (d, J=3.5 Hz, 1H), 4.38 (d, J=3.9 Hz, 1H), 3.14 (d, J=9.8 Hz, 1H),3.05 (d, J=9.6 Hz, 1H), 1.57 (ddq, J=17.7, 6.8, 4.1, 3.1 Hz, 4H).

Example 2: Synthesis of(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Compound 118) and Isolation of Enantiomers Step 1. Preparation ofmethyl 7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (Intermediate I7)

A solution of I-2 (1.00 g, 4.29 mmol) in water (10 mL) was cooled to 0°C. and was treated with acetic acid (1.23 mL). Zinc dust (421 mg, 6.44mmol) was added over the course of 2 minutes and the mixture was allowedto warm to RT over 10 min. LCMS indicated the reaction to be complete.The reaction was diluted with EtOAc, washed with sat. aq. NaHCO₃ andbrine, dried (MgSO₄), filtered, and concentrated. The resulting residuewas taken up in DCM and purified by FCC (80 g, 0-80% EtOAc, 30 min) toafford the desired 17 (1.18 g, 85% yield). LCMS m/z (M+1, 155.2); ¹H NMR(400 MHz, DMSO) δ 7.11 (s, 1H), 5.10 (d, J=4.4 Hz, 2H), 3.69 (s, 3H),1.82-1.69 (m, 2H), 1.24-1.13 (m, 2H).

Step 2. Preparation of 1R,2R,3S,4S)-methyl3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylate (IntermediateI-8)

A solution of I-7 (200 mg, 1.297 mmol), BINAP (72.7 mg, 0.117 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (559 mg, 2.72mmol), K₂CO₃ (90 mg, 0.649 mmol), and RhCl(cod)₂ (12 mg, 1.297 mmol) indioxane (12 mL)/water (4 mL) was evacuated and purged with argon twiceand then warmed at 100° C. for 60 min in a microwave reactor. LCMSshowed mostly product mass with small amounts of I-9 near the solventfront. The reaction was diluted with EtOAc, washed with water and brine,dried (Na₂SO₄), filtered, and concentrated. The resulting residue wastaken up in DCM and purified by FCC (DCM/EtOAc) to afford the desiredproduct Intermediate I-8 as a 4:1 mixture of trans:cis (261 mg, 82%).LCMS m/z (M+1, 234.2). ¹H NMR of 4:1 mixture (400 MHz, DMSO) δ 8.47 (d,J=6.1 Hz, 2H), 8.41 (d, J=6.1 Hz, 0.5H), 7.29 (d, J=6.1 Hz, 2H), 7.20(d, J=6.1 Hz, 0.5H), 4.89-4.81 (m, 1.3H), 4.53 (d, J=4.7 Hz, 1H), 4.50(d, J=4.1 Hz, 0.3H), 3.65 (s, 3.8H), 3.44 (d, J=9.8 Hz, 0.3H), 3.30-3.27(m, 1.3H), 3.12-3.05 (m, 1H), 1.78-1.52 (m, 5H).

Step 3: Preparation of(1R,2R,3S,4S)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylicacid (Intermediate I-9)

A solution of a I-8 (4:1 mixture of trans:cis, 168 mg, 0.720 mmol) inTHF (3 mL), MeOH (2 mL) and water (1 mL) was treated with LiOH (103 mg,4.32 mmol) and stirred at 80° C. for 2 hours. LCMS showed the reactionto be complete. The solution was taken to pH 3 with HCl and wasconcentrated under reduced pressure. The resulting residue, IntermediateI-9, was dried under vacuum overnight and was used directly in the nextstep without purification assuming quantitative yield. LCMS m/z (M+1,220.2).

Alternatively, I-9 may be synthesis from I-7 in a one pot reaction:

A solution of I-7 (200 mg, 1.297 mmol), BINAP (72.7 mg, 0.117 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (559 mg, 2.72mmol), K₂CO₃ (90 mg, 0.649 mmol), and RhCl(cod)₂ (12 mg, 1.297 mmol) indioxane (12 mL)/water (4 mL) was evacuated and purged with argon twiceand then warmed at 100° C. for 60 min in a microwave reactor. LCMSshowed mostly I-8 was present with small amounts of I-9. The reactionwas repeated 7 times on the same scale to the same result (total of 1.6grams of I-7 used, 10.38 mmol). The reactions were combined, dilutedwith MeOH (200 mL) and THF (200 mL), and treated with LiOH (746 mg, 31.1mmol). The reaction was stirred at RT for 2 hours. LCMS showed no changein the ratio of I-9:I-8. Another 746 mg LiOH (31.1 mmol) was added andthe reaction was warmed at 80° C. for 1 h. LCMS showed an approximate1:2 ratio of I-9:I-8. Another 746 mg LiOH (31.1 mmol) was added and thereaction was stirred for 1 hour at 80° C. LCMS showed the reaction wascomplete. The resulting solution was concentrated under reduced pressureand dried under vacuum overnight. The resulting residue containingproduct and inorganic solids was taken up in 300 mL of 1:1 DCM:MeOH,celite was added, and the solution was concentrated. The celite mixturewas loaded onto a column and the product was eluted (80 g column, 0-90%MeOH/DCM, 35 min) to afford the desired acid product with a large amountof silica gel (7.8 grams crude mass; 2.28 grams was theoretical). Theproduct mixture was used in the next step as is assuming only 25% of themass corresponded to the desired acid product. (Note: I-9 is watersoluble under basic, neutral, and acidic workup conditions and thereforeno workup was performed). LCMS m/z (M+1, 220.2).

Step 4. Preparation of Compound 118

A suspension of I-9 (90 mg, 0.411 mmol) (360 mg including SiO₂),3,4-dichloroaniline (100 mg, 0.616 mmol), and T3P (0.489 mL, 0.821 mmol)in ethyl acetate (8 mL) was treated with DIEA (0.215 mL, 1.232 mmol).After 5 minutes of stirring at 23° C., the solution remained asuspension. DMF (3 mL) was added and only a slight precipitate remained.The reaction was stirred for 30 minutes at RT, after which LCMS showed1:1 SM:product. The reaction was warmed at 80° C. for 20 minutes andLCMS showed the same ratio of SM to product. Additional T3P (0.489 mL,0.821 mmol) and DIEA (0.43 mL, 6 equiv) were added and the reaction wascontinued at 80° C. for 40 additional minutes. LCMS showed the reactionto be at ˜90% conversion. The reaction was stirred for another 1 hour at80° C. then was cooled to room temperature. An identical reaction wasrun on 1.0 grams of I-9 (4.0 grams including mass of SiO₂), 10.8 mL ofT3P (4 equiv), 7.17 mL DIEA (9 equiv), in 100 mL of EtOAc and 30 mL ofDMF. The reaction was warmed at 80° C. for 45 minutes and was judged tobe complete by LCMS. After cooling to RT, the two reactions werecombined and diluted with EtOAc, washed with water and brine, dried(Na₂SO₄), filtered, and concentrated. The residue was purified bychromatography (80 g gold column, 0-70% EtOAc/DCM for 20 minutes, then0-40% MeOH/DCM for 20 minutes) to afford the desired product Compound118 (1.34 g, 3.50 mmol, 74% yield) as a white solid.

Compound 118 was purified by recrystallation. The solid was dissolved in˜150 mL of MeCN and was heated to reflux until the solid completelydissolved. The solution was placed in a −20° C. freezer overnight. Thecrystals were filtered off and washed with cold MeCN to obtain 1.05grams of an off-white crystallized solid. The mother liquor wasconcentrated and recrystallized from MeCN in identical fashion to afford0.155 g additional Compound 118 (˜93% recovery overall). Both batches ofmaterial were pure by ¹H NMR and were dried under high vacuum. Meltingpoint was determined to be 228-230° C. (10° C./min, uncorrected).

Chiral separation of 155 mg of Compound 118 afforded 66.9 mg of(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Compound 71) (peak 1) and 62.9 mg of(1S,2S,3R,4R)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Compound 103) (peak 2) after recrystallization of both enantiomers fromMeCN. LCMS m/z (M+1, 363.1); ¹H NMR (400 MHz, DMSO) δ 10.35 (s, 1H),8.48 (dd, J=4.4, 1.6 Hz, 2H), 8.01 (d, J=2.4 Hz, 1H), 7.57 (d, J=8.8 Hz,1H), 7.43 (dd, J=8.8, 2.4 Hz, 1H), 7.27 (dd, J=4.5, 1.7 Hz, 2H), 4.93(t, J=5.1 Hz, 1H), 4.59 (d, J=4.3 Hz, 1H), 3.39 (d, J=5.0 Hz, 1H), 3.07(td, J=5.1, 1.5 Hz, 1H), 1.80-1.49 (m, 4H).

Example 3. Synthesis of(1R,4S)—N-(2-chloro-[1,1′-biphenyl]-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide(Compound 160)

Step 1. Preparation of methyl3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate I-10)

A dioxane (10 mL) suspension of methyl3-bromo-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate I-2 (356 mg, 1.526mmol),2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine(500 mg, 1.831 mmol) and tetrakis (176 mg, 0.153 mmol) was treated withsodium carbonate (1.144 mL, 2.289 mmol, 2M solution). The reactionmixture was purged with nitrogen and heated in microwave reactor for 45min at 120° C. AcOEt was added and washed with water. The organic phasewas concentrated and purified by FCC (0 to 40% EtOAc/hex) to give ayellow syrup as the desired product Intermediate I-10 (295 mg, 61%).LCMS m/z (M+1, 300.0).

Step 2. Preparation of3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylicacid (Intermediate I-11)

A solution of I-10 (290 mg, 0.969 mmol) in MeOH (5 mL) was treated withlithium hydroxide (1.938 mL, 1.938 mmol, 1N solution) and stirred at RTfor 6 hr. The reaction mixture was acidified with AcOH to pH 5-6. Awhite solid was precipitated. Filtration followed by washed with watergave a white solid as the desired product Intermediate I-11 (220 mg,76%). LCMS m/z (M+1, 286.0).

Step 3. Preparation of Compound 160

A EtOAc (3 mL) solution of I11 (40 mg, 0.140 mmol) and2-chloro-[1,1′-biphenyl]-4-amine (28.6 mg, 0.140 mmol) was treated withpropanephosphonic anhydride (0.427 mL, 0.701 mmol). After addition, thesolution was heated to 80° C. overnight. The reaction was diluted withEtOAc, washed with sat. aq. NaHCO₃, dried (Na₂SO₄), filtered, andconcentrated. The resulting residue was purified by FCC (0 to 60%AcOEt/hex) to give a solid as the desired product Compound 160 (42 mg,57% yield). ¹H NMR (400 MHz, CDCl₃) δ 11.70 (s, 1H), 8.09 (d, J=8.0,1H), 7.89 (d, J=2.1, 1H), 7.82-7.73 (m, 1H), 7.67-7.53 (m, 2H),7.51-7.39 (m, 5H), 7.35 (d, J=8.4, 1H), 5.76-5.59 (m, 1H), 5.59-5.44 (m,1H), 2.28-2.11 (m, 2H), 1.76 (t, J=8.4, 1H), 1.65 (d, J=8.8, 1H); LCMSm/z (M+1, 471.1).

Example 4.(1R,2R,3R,4S)—N-(3,4-dichlorophenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Compound 155)

A solution ofN-(3,4-dichlorophenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide(22 mg, 0.051 mmol) and 5% palladium on carbon (20 mg) was hydrogenatedat 1 atm for 16 h. The reaction was filtered over celite and washed withEtOAc. The solvent was concentrated and the crude compound was purifiedby HPLC (10-90% ACN/water) to afford the desired product Compound 155(20 mg, 86%). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (t, J=7.8, 1H), 7.51 (t,J=9.7, 2H), 7.35-7.27 (m, 3H), 7.11 (dd, J=2.3, 8.7, 1H), 4.98-4.86 (m,2H), 3.92 (dd, J=4.5, 11.3, 1H), 3.52 (dd, J=5.1, 11.4, 1H), 2.39 (t,J=8.6, 1H), 1.99 (t, J=8.4, 1H), 1.78 (dd, J=4.6, 8.0, 2H); LCMS m/z(M+1, 431.1).

Example 5. Synthesis of(1R,2S,3R,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Compound 134)

To(1R,2R,3R,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide156 (5 mg, 0.012 mmol) was added morpholine (1 mL) and the reaction washeated to 80° C. overnight. The reaction mixture was purified directlywith HPLC (20 to 90% ACN/water) to afford the desired product Compound134 (3.0 mg, 54%). ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.78 (t,J=1.3, 1H), 7.40 (d, J=1.4, 2H), 6.49 (s, 1H), 4.91 (dd, J=5.2, 10.9,2H), 3.93 (s, 3H), 3.78-3.65 (m, 1H), 2.83 (d, J=5.2, 1H), 2.06-1.91 (m,1H), 1.74-1.61 (m, 3H); LCMS m/z (M+1, 438.1).

Example 6. Synthesis of(1R,2R,4S,5S)—N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-4-yl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide(Compound 85) Step 1. Preparation of (1R,2R,4S,5S)-tert-butyl4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxylate(Intermediate I-13)

A solution of trimethylsulfoxonium iodide (483 mg, 2.195 mmol) in DMSO(7.3 mL) was treated with 60% NaH in mineral oil (88 mg, 2.195 mmol) andwas stirred at room temperature for 30 min (gas evolution had ceased).Intermediate I-12 (200 mg, 0.732 mmol) in 7.0 mL DMSO was added dropwiseand the resulting mixture was warmed at 50° C. for 16 hr. The reactionwas diluted with EtOAc, washed with water and brine, dried (Na2SO4),filtered, and concentrated to afford the desired product, IntermediateI-13, (200 mg, 90%). LCMS m/z (M+1, 288.3).

Step 2. Preparation of(1R,2R,4S,5S)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxylicacid (Intermediate I-14)

A solution of I-13 (195 mg, 0.679 mmol) in DCM (Volume: 5 mL) at 23° C.was treated with TFA (5 mL, 64.9 mmol) and stirred for 2 h. Thevolatiles were removed under a stream of nitrogen, and the resultingresidue was azeotroped with toluene twice to afford the desired productIntermediate I-14 as the TFA salt (234 mg, 95%). LCMS m/z (M+1, 232.1).

Step 3. Preparation of Compound 85

A solution of I-14 (15 mg, 0.065 mmol), amine (21.6 mg, 0.097 mmol) andHATU (49 mg, 0.130 mmol) in EtOAc (1 mL) was treated with DIEA (0.034ml, 0.195 mmol) and the reaction mixture was stirred at 70° C. for 5 h.The reaction was diluted with EtOAc, washed with water and brine, dried(Na2SO4), filtered, and concentrated. The residue was purified by FCC toafford the desired product Compound 85 (9.7 mg, 31%). ¹H NMR (400 MHz,MeOD) δ 8.47-8.43 (m, 2H), 7.70-7.17 (m, 9H), 4.79 (d, J=4.7 Hz, 1H),4.65 (d, J=4.8 Hz, 1H), 2.45 (ddd, J=11.5, 9.1, 4.0 Hz, 1H), 2.04-1.96(m, 1H), 1.88 (d, J=4.9 Hz, 1H), 1.83 (dt, J=11.3, 4.4 Hz, 1H),1.79-1.69 (m, 1H), 1.26 (d, J=4.8 Hz, 1H); LCMS m/z (M+1, 435.2).

Example 7. Synthesis of(1S,2S,3R,4R)-3-cyano-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Compound 77) Step 1. Preparation of(1R,2S,3R,4S)-3-((3,4-dichlorophenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylicacid (Intermediate I-16)

A solution of I-15 from Alfa Aesar (500 mg, 2.97 mmol) and3,4-dichloroaniline (482 mg, 2.97 mmol) in THF (Volume: 25 mL) wasstirred at 23° C. for 16 hr. A precipitate had formed. The reaction wasfiltered to afford I-16 (368 mg, 35%). LCMS m/z (M+1, 330.0).

Step 2. Preparation of(1R,2S,3S,4S)-3-((3,4-dichlorophenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylicacid (Intermediate I-17)

A solution of I-16 (300 mg, 0.909 mmol) in THF (6 mL) and water (6 mL)was treated with LiOH (218 mg, 9.09 mmol) and the solution was warmed at80° C. for 16 hr. LCMS indicated complete product formation. Thereaction mixture was acidified with 1 N HCl, diluted with EtOAc, washedwith water and brine, dried (Na2SO4), filtered, and concentrated toafford I-17 (300 mg, 95%). LCMS m/z (M+1, 330.1).

Step 3. Preparation of(1R,2S,3S,4S)-3-((3,4-dichlorophenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylicacid (Intermediate I-18)

A solution of I-17 (100 mg, 0.303 mmol) in tetrahydrofuran (1212 μl) wastreated with DIEA (58.2 μl, 0.333 mmol) and isobutyl chloroformate (43.6μl, 0.333 mmol) and was stirred at RT for 30 minutes. Ammonium hydroxide(126 μl, 0.909 mmol) was added and the reaction was stirred for 30minutes. LCMS showed the desired product in approximately an equal ratioto starting material. The reaction repeated with 200 mg I-17 to the sameresult. The two batches were combined, washed with water and brine,dried (Na2SO4), filtered, and concentrated. The resulting residue wasattempted to be purified by FCC; however, the intented productIntermediate I-18 could not be separated from unreacted startingmaterial. The product containing fractions were combined, concentrated,and carried forward to the next reaction as is.

Step 4. Preparation of Compound 77

A solution of I-18 (100 mg, 0.304 mmol) in DCM (Volume: 2 mL) wastreated with TFAA (0.064 mL, 0.456 mmol) and DIEA (0.106 mL, 0.608 mmol)and was stirred at 23° C. for 4 hr. LCMS showed product formation alongwith SM carboxylic acid from the previous reaction. The volatiles wereremoved under a stream of nitrogen and the residue was purified by FCCto afford the desired product nitrile, Compound 77, (58 mg, 58%). LCMSm/z (M+1, 311.1).

By repeating the procedures described in the general procedures and theabove examples, using appropriate starting materials, the followingcompounds of Formula I, as identified in Table 3 below, were obtained.

It is understood that if there appears to be a discrepancy between thename and structure of a particular compound, the structure is to beconsidered correct as the compound names were generated from thestructures.

It is further understood that, unless specifically identified, thestructure depicted in Table represents a mixture of the enantiomers.

TABLE 3 Exemplified Compounds of Formula I of the Invention PhysicalData Ex. MS (m/z), Elemental Analysis, ¹H NMR, No. Structure MeltingPoint, HPLC RT 1

¹H NMR (400 MHz, MeOD) δ 7.88 (d, J = 5.4 Hz, 1H), 7.83-7.81 (m, 2H),7.33 (d, J = 1.8 Hz, 1H), 6.97 (s, 1H), 6.83 (d, J = 5.7 Hz, 1H), 4.82(t, J = 5.2 Hz, 1H), 4.52 (d, J = 4.7 Hz, 1H), 3.36 (d, J = 5.0 Hz, 1H),2.97 (td, J = 5.2, 1.5 Hz, 1H), 1.78-1.60 (m, 4H), 1.22 (t, J = 7.4 Hz,3H). LCMS m/z 472.2. RT 2.17 min. (5 min) (C18, 20-90%, water (0.05%TFA)/ACN) 2

¹H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.01 (dd, J = 1.0, 8.4 Hz, 1H),7.83 (d, J = 1.6, 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.54 (d, J =8.0 Hz, 2H), 7.47- 7.40 (m, 1H), 7.11-7.05 (m, 1H), 5.11 (s, 1H), 4.98(s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.04 (d, J = 9.6 Hz, 1H), 3.44 (d, J= 9.6 Hz, 1H), 1.78-1.71 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H). LCMS m/z(M + 1, 468.12). RT 1.66 min. (3.5 min) (C18, 20-100%, water (0.05%TFA)/ACN) 3

¹H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 10.10 (s, 2H), 8.01 (d, J = 2.4Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 2.4, 8.9 Hz, 1H), 7.43(s, 1H), 4.84 (t, J = 5.1 Hz, 1H), 4.38 (d, J = 4.5 Hz, 1H), 3.29 (d, J= 4.7 Hz, 1H), 3.00 (t, J = 4.5 Hz, 1H), 1.69-1.48 (m, 4H). LCMS m/z(M + 1), 352.05). RT 2.22 min. (5 min) (C18, 10-90%, water (0.05%TFA)/ACN) 4

¹H NMR (600 MHz, DMSO) δ = 10.37 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.58(d, J = 8.8 Hz, 1H), 7.45 (dd, J = 2.5, 8.8 Hz, 1H), 7.29 (d, J = 1.8Hz, 1H), 6.07 (d, J = 1.8 Hz, 1H), 4.90 (t, J = 5.2 Hz, 1H), 4.60-4.55(m, 1H), 3.50 (d, J = 5.0 Hz, 1H), 3.05 (td, J = 1.4, 5.2 Hz, 1H), 1.73-1.52 (m, 4H). LCMS m/z (M + 1, 366.07). RT 1.61 min. (3.5 min) (C18,10-90%, water (0.05% TFA)/ACN) 5

¹H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.72(d, J = 5.3 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 8.8, 2.4Hz, 1H), 6.31 (dd, J = 5.3, 1.4 Hz, 1H), 6.25 (s, 1H), 5.78 (s, 2H),4.79 (t, J = 5.0 Hz, 1H), 4.46 (d, J = 4.7 Hz, 1H), 3.09 (d, J = 5.1 Hz,1H), 2.92 (t, J = 4.7 Hz, 1H), 1.65-1.47 (m, 4H). LCMS m/z (M + 1,378.07). RT 1.54 min. (3.5 min) (C18, 10-100%, water (0.05% TFA)/ACN) 6

¹H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.44(d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.12 (s, 1H), 7.10 (dd, J = 2.4, 8.8Hz, 1H), 4.82 (d, J = 3.2 Hz, 1H), 4.32 (d, J = 4.8 Hz, 1H), 3.59 (s,3H), 3.37 (d, J = 9.4 Hz, 1H), 2.99 (d, J = 9.4 Hz, 1H), 1.71- 1.55 (m,4H). LCMS m/z (M + 1, 366.07). RT 1.46 min. (5 min) (C18, 10-90%, water(0.05% TFA)/ACN) 7

LCMS m/z (M + 1, 366.07). RT 2.23 min. (5 min) (C18, 10-90%, water(0.05% TFA)/ACN) 8

¹H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 8.28 (d, J = 6.0 Hz, 2H), 7.41(d, J = 2.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 6.1 Hz, 2H),6.99 (dd, J = 8.8, 2.4 Hz, 1H), 4.89 (d, J = 3.4 Hz, 1H), 4.53 (d, J =4.2 Hz, 1H), 3.44 (d, J = 9.7 Hz, 1H), 3.21 (d, J = 9.8 Hz, 1H),1.75-1.63 (m, 4H). Calc. C, 59.52; H, 4.44; Cl, 19.52; N, 7.71; O, 8.81.Found C, 59.66; H, 4.46; N, 7.75. LCMS m/z (M + 1, 363.06). RT 1.26 min.(2 min) (C18, 10-100%, water (0.05% TFA)/ACN) 9

¹H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H), 8.04(d, J = 2.3 Hz, 1H), 7.80-7.73 (m, 3H), 7.59-7.54 (m, 2H), 7.51 (d, J =8.7 Hz, 2H), 7.46- 7.42 (m, 2H), 7.38-7.33 (m, 1H), 5.14 (s, 1H), 5.01(s, 1H), 4.06 (t, J = 9.2 Hz, 1H), 3.89 (s, 3H), 3.47 (d, J = 9.7 Hz,1H), 1.78-1.74 (m, 4H). LCMS m/z (M + 1, 530.14). RT 3.11 min. (5 min)(C18, 20-90%, water (0.05% TFA)/ACN) 10

¹H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.79(d, J = 5.3 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.8, 2.4Hz, 1H), 6.39 (dd, J = 5.3, 1.4 Hz, 1H), 6.33 (s, 2H), 5.85 (s, 1H),4.86 (s, 1H), 4.54 (d, J = 4.7 Hz, 1H), 3.17 (d, J = 5.2 Hz, 1H), 2.99(t, J = 4.7 Hz, 1H), 1.70-1.53 (m, 4H). Calc. C, 57.16; H, 4.53; Cl,18.75; N, 11.11; O, 8.46. Found C, 57.29; H, 5.03; N, 10.42. LCMS m/z(M + 1, 378.07). RT 1.51 min. (3.5 min) (C18, 10-100%, water (0.05%TFA)/ACN) 11

¹H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 8.28 (d, J = 6.0 Hz, 2H), 7.41(d, J = 2.4 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 6.1 Hz, 2H),6.99 (dd, J = 8.8, 2.5 Hz, 1H), 4.89 (d, J = 3.4 Hz, 1H), 4.53 (d, J =4.1 Hz, 1H), 3.44 (d, J = 9.7 Hz, 1H), 3.21 (d, J = 9.7 Hz, 1H),1.74-1.62 (m, 4H). Calc. C, 59.52; H, 4.44; 01, 19.52; N, 7.71; O, 8.81.Found C, 59.64; H, 4.52; N, 7.67. LCMS m/z (M + 1, 363.06). RT 1.27 min.(3.5 min) (C18, 10-100%, water (0.05% TFA)/ACN) 12

¹H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.56(dd, J = 3.3, 5.5 Hz, 2H), 7.47 (dd, J = 2.5, 8.8 Hz, 1H), 6.07 (d, J =2.2 Hz, 1H), 4.81 (t, J = 5.2 Hz, 1H), 4.50 (d, J = 4.8 Hz, 1H), 3.74(s, 3H), 3.41-3.38 (m, 1H), 3.36 (d, J = 4.9 Hz, 1H), 1.69- 1.57 (m,4H). LCMS m/z (M + 1, 366.07). RT 2.39 min. (5 min) (C18, 10-100%, water(0.05% TFA)/ACN) 13

¹H NMR (600 MHz, DMSO) δ 9.59 (s, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.43(d, J = 8.8 Hz, 1H), 7.12-7.06 (m, 2H), 6.02 (d, J = 1.9 Hz, 1H), 4.87(d, J = 4.3 Hz, 1H), 4.46 (s, 1H), 3.63 (d, J = 9.5 Hz, 1H), 3.13 (d, J= 9.6 Hz, 1H), 1.72-1.58 (m, 4H). LCMS m/z (M + 1), 366.07). RT 1.50min. (3.5 min) (C18, 10-90%, water (0.05% TFA)/ACN) 14

¹H NMR (400 MHz, MeOD) δ 8.47 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 1.7 Hz,1H), 7.47 (dd, J = 5.3, 1.5 Hz, 1H), 7.43 (d, J = 2.5 Hz, 2H), 7.38 (s,1H), 4.95 (t, J = 5.2 Hz, 1H), 4.66 (d, J = 4.6 Hz, 1H), 3.60 (d, J =4.9 Hz, 1H), 3.11 (td, J = 5.2, 1.4 Hz, 1H), 2.55 (q, J = 7.3 Hz, 4H),1.89-1.70 (m, 4H), 1.08 (t, J = 7.3 Hz, 6H). LCMS m/z (M + 1, 490.12).RT 2.66 min. (5 min) (C18, 20-90%, water (0.05% TFA)/ACN) 15

¹H NMR (400 MHz, DMSO) δ 10.29 (s, 1H), 10.07 (s, 1H), 8.08 (d, J = 5.2Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 7.50 (d, J = 8.8 Hz,1H), 7.37 (dd, J = 8.8, 2.4 Hz, 1H), 3.30-3.28 (m, 1H), 6.88 (dd, J =5.2, 1.4 Hz, 1H), 4.85 (t, J = 5.0 Hz, 1H), 4.48 (d, J = 4.3 Hz, 1H),3.59 (s, 3H), 3.01 (t, J = 4.7 Hz, 1H), 1.66- 1.50 (m, 4H). LCMS m/z(M + 1, 436.08). RT 1.51 min. (3.5 min) (C18, 10-100%, water (0.05%TFA)/ACN) 16

¹H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 10.29 (s, 1H), 8.12 (d, J = 5.2Hz, 1H), 8.01 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.8 Hz,1H), 7.37 (dd, J = 8.8, 2.4 Hz, 1H), 6.91 (dd, J = 5.2, 1.5 Hz, 1H),4.85 (t, J = 5.1 Hz, 1H), 4.47 (d, J = 4.3 Hz, 1H), 3.29 (s, 1H), 3.01(t, J = 4.6 Hz, 1H), 2.30 (q, J = 7.5 Hz, 2H), 1.66- 1.48 (m, 4H), 0.98(t, J = 7.5 Hz, 3H). LCMS m/z (M + 1, 434.10). RT 1.80 min. (5 min)(C18, 20-90%, water (0.05% TFA)/ACN) 17

¹H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.80(d, J 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H),5.10 (s, 1H), 4.88 (d, J = 2.8 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.90(d, J = 9.4 Hz, 1H), 3.41 (d, J = 9.4 Hz, 1H), 1.76-1.65 (m, 4H), 1.28(t, J = 7.2 Hz, 3H). LCMS m/z (M + 1, 468.12). RT 2.50 min. (5 min)(C18, 20-90%, water (0.05% TFA)/ACN) 18

LCMS m/z (M + 1, 347.0) 19

¹H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.25 (s, 2H), 7.99 (d, J = 2.4Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.8, 2.4 Hz, 1H), 4.91(t, J = 5.1 Hz, 1H), 4.45 (d, J = 4.2 Hz, 1H), 3.24 (d, J = 4.9 Hz, 1H),3.10 (s, 6H), 3.08-2.97 (m, 1H), 1.82-1.44 (m, 4H). LCMS m/z (M + 1,407.1) 20

¹H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.52 (dd, J = 5.2, 0.8 Hz, 1H),7.76-7.60 (m, 1H), 7.50-7.02 (m, 8H), 4.88 (t, J = 4.8 Hz, 1H), 4.78 (t,J = 4.9 Hz, 1H), 3.68-3.46 (m, 2H), 1.94 (ddd, J = 11.9, 8.9, 3.2 Hz,1H), 1.77 (ddd, J = 12.0, 8.8, 5.2 Hz, 1H), 1.70- 1.41 (m, 2H). LCMS m/z(M + 1, 432.1) 21

LCMS m/z (M + 1, 410.1) 22

¹H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.06 (s, 1H), 8.70 (s, 2H), 7.99(d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.8, 2.5Hz, 1H), 4.99 (t, J = 5.1 Hz, 1H), 4.60 (d, J = 4.0 Hz, 1H), 3.47 (d, J= 4.8 Hz, 1H), 3.16 (td, J = 5.2, 1.6 Hz, 1H), 1.80~1.52 (m, , 4H). LCMSm/z (M + 1, 364.0) 23

LCMS m/z (M + 1, 407.1) 24

LCMS m/z (M + 1, 387.0) 25

LCMS m/z (M + 1, 405.1) 26

¹H NMR (400 MHz, DMSO) δ 8.40 (d, J = 5.6 Hz, 2H), 7.7 (s, 1H), 7.54(dd, J = 12.0 2.0 Hz, 1H), 7.43~7.38 (m, 1H), 7.28~7.16 (m, 7H), 4.83(dd, J = 5.2 5.2 Hz, 1H), 4.58 (d, J = 4.8 Hz, 1H), 3.40 (d, J = 4.8 Hz,1H), 2.90 (ddd, J = 5.2, 5.2, 1.2 Hz, 1H), 2.01~1.94 (m, 1H), 1.86~1.64(m, 3H). LCMS m/z (M + 1, 423.0) 27

LCMS m/z (M + 1, 491.1) 28

¹H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 8.07- 7.99 (m, 1H), 7.83 (dd, J= 12.6, 2.0 Hz, 1H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.39-7.25 (m, 2H),6.81 (d, J = 2.0 Hz, 1H), 5.61 (d, J = 3.9 Hz, 1H), 5.44 (d, J = 2.7 Hz,1H), 1.96-1.87 (m, 1H), 1.51-1.27 (m, 2H). LCMS m/z (M + 1, 394.1) 29

¹H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.55(d, J = 8.8 Hz, 1H), 7.50-7.34 (m, 5H), 6.04 (s, 1H), 4.93 (t, J = 5.1Hz, 1H), 4.58 (d, J = 3.9 Hz, 1H), 3.45 (d, J = 5.0 Hz, 1H), 3.15-3.08(m, 1H), 2.51 (p, J = 1.9 Hz, 2H), 2.27 (d, J = 0.8 Hz, 3H), 2.17 (s,3H), 1.80~1.51 (m, 4H). LCMS m/z (M + 1, 456.1) 30

¹H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.70(d, J = 2.6 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H),7.37 (dd, J = 8.8, 2.4 Hz, 1H), 6.79 (t, J = 2.3 Hz, 1H), 5.16 (s, 2H),4.81 (t, J = 5.1 Hz, 1H), 4.43 (d, J = 4.3 Hz, 1H), 3.25~3.15 (m, 1H),2.95 (td, J = 5.2, 1.6 Hz, 1H), 1.70~1.43 (m, 4H). LCMS m/z (M + 1,378.0) 31

LCMS m/z (M + 1, 494.1) 32

LCMS m/z (M + 1, 419.1) 33

¹H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.48 (d, J = 3.6 Hz. 2H), 7.69(dd, J = 11.9, 2.4 Hz, 1H), 7.42 (t, J = 8.6 Hz, 1H), 7.23 (ddd, J =8.8, 2.4, 1.1 Hz, 1H), 7.19 (d, J = 6.1 Hz, 2H), 4.86 (t, J = 5.1 Hz,1H), 4.51 (d, J = 4.3 Hz, 1H), 3.33 (d, J = 5.0 Hz, 1H), 3.01 (td, J =5.2, 1.6 Hz, 1H), 1.78-1.36 (m, 4H). LCMS m/z (M + 1, 347.0) 34

LCMS m/z (M + 1, 407.1) 35

LCMS m/z (M + 1, 405.0) 36

¹H NMR (400 MHz, DMSO) δ 8.42 (d, J = 5.2 Hz, 2H), 7.77 (d, J = 8.8 Hz,2H), 7.70-7.54 (m, 3H), 7.39 (dd, J = 8.4, 6.9 Hz, 2H), 7.29 (tt, J =8.0, 1.2 Hz, 1H), 7.19 (d, J = 6.3 Hz, 2H), 6.72 (d, J = 5.8 Hz, 1H),6.22 (dd, J = 5.8, 1.7 Hz, 1H), 5.30 (dd, J = 4.6, 1.7 Hz, 1H), 4.61 (d,J = 11.8 Hz, 1H), 4.11 (d, J = 11.8 Hz, 1H), 3.69 (t, J = 4.3 Hz, 1H),3.11 (d, J = 4.2 Hz, 1H). LCMS m/z (M + 1, 381.1) 37

LCMS m/z (M + 1, 379.0) 38

LCMS m/z (M + 1, 371.1) 39

¹H NMR (400 MHz, DMSO) δ 8.55 (d, J = 5.6 Hz, 2H), 8.00 (d, J = 2.0 Hz,1H), 7.60~7.40 ( m, 8H), 7.37~ 7.33 (m, 2H), 5.01 (dd, J = 4.8, 4.8 Hz,1H), 4.66 (d, J = 4.4 Hz, 1H), 3.48 (d, J = 5.2 Hz, 1H), 3.15 (brt, J =5.2 Hz, 1H), 1.85~1.74 (m, 3H), 1.71~1.60 (m, 1H). LCMS m/z (M + 1,405.1) 40

¹H NMR (400 MHz, DMSO) δ 10.18 (brs, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.69(d, J = 2.5 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.8, 2.4Hz, 1H), 7.22 (dd, J = 8.5, 2.5 Hz, 1H), 6.34 (brd, J + 8.4 Hz, 1H),5.59 (s, 2H), 4.79 (t, J = 5.1 Hz, 1H), 4.32 (d, J = 4.2 Hz, 1H), 3.11(d, J = 5.0 Hz, 1H), 2.92 (td, J = 5.2, 1.5 Hz, 1H), 1.70-1.36 (m, 4H).LCMS m/z (M + 1, 378.0) 41

LCMS m/z (M + 1, 347.1) 42

¹H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.67 (dd, J = 5.1, 0.8 Hz, 1H),7.99 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 1.4 Hz, 1H), 7.62 (dd, J = 5.1,1.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.8, 2.5 Hz, 1H),4.98 (t, J = 5.1 Hz, 1H), 4.64 (d, J = 4.6 Hz, 1H), 3.53 (d, J = 4.9 Hz,1H), 3.12 (td, J = 5.2, 1.6 Hz, 1H), 1.85-1.46 (m, 4H). LCMS m/z (M + 1,388.1) 43

LCMS m/z (M + 1, 451.1) 44

LCMS m/z (M + 1, 439.1) 45

¹H NMR (400 MHz, DMSO) δ 9.68 (s, 1H), 8.61 (dd, J = 13.9, 2.1 Hz, 2H),8.15 (t, J = 2.4 H, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz,1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 4.83 (d, J = 3.4 Hz, 1H), 4.53 (d,J = 4.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.52 (d, J = 9.6 Hz, 1H),3.20~3.12 (m, 1H), 1.87-1.40 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H). LCMS m/z(M + 1, 435.1) 46

¹H NMR (400 MHz, DMSO) δ 10.6 (s, 1H), 7.77 (dd, J = 12.4, 2.0 Hz, 1H),7.58 (dd, J = 8.4, 2.0 Hz, 1H), 7.52~7.44 (m, 3H), 7.37~7.29 (m, 2H),5.69 (d, J = 4.4 Hz, 1H), 5.49 (d, J = 4.0 Hz, 1H), 2.24~1.86 (m, 2H),1.54~1.42 (m, 2H). LCMS m/z (M + 1, 353.1) 47

LCMS m/z (M + 1, 392.1) 48

¹H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.62(d, J = 2.2 Hz, 1H), 8.11 (t, J = 2.0 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H),7.47 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.8, 2.5 Hz, 1H), 4.91 (t, J =5.1 Hz, 1H), 4.48 (dd, J = 3.3, 1.6 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H),3.47 (d, J = 4.8 Hz, 1H), 3.06 (td, J = 5.2, 1.6 Hz, 1H), 1.77-1.33 (m,4H), 1.27 (t, J = 7.1 Hz, 2H). LCMS m/z (M + 1, 435.0) 49

LCMS m/z (M + 1, 420.1) 50

LCMS m/z (M + 1, 476.1) 51

LCMS m/z (M + 1, 395.1) 52

LCMS m/z (M + 1, 407.1) 53

LCMS m/z (M + 1, 364.0) 54

LCMS m/z (M + 1, 385.0) 55

LCMS m/z (M + 1, 371.1) 56

LCMS m/z (M + 1, 430.1) 57

LCMS m/z (M + 1, 371.1) 58

¹H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 8.41 (dd, J = 4.4, 1.6 Hz, 2H),7.57 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.25-6.94 (m, 3H),4.87 (t, J = 5.1 Hz, 1H), 4.51 (d, J = 4.0 Hz, 1H), 4.16 (q, J = 7.1 Hz,2H), 3.71-3.55 (m, 4H), 3.34 (d, J = 5.0 Hz, 1H), 3.05-3.00 (m, 1H),2.92-2.80 (m, 4H), 1.75-1.46 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H). LCMS m/z(M + 1, 452.1) 59

LCMS m/z (M + 1, 388.0) 60

LCMS m/z (M + 1, 355.1) 61

LCMS m/z (M + 1, 373.1) 62

LCMS m/z (M + 1, 478.1) 63

LCMS m/z (M + 1, 379.0) 64

LCMS m/z (M + 1, 422.1) 65

LCMS m/z (M + 1, 460.1) 66

LCMS m/z (M + 1, 378.0) 67

LCMS m/z (M + 1, 383.1) 68

¹H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 10.26 (s, 1H), 8.09 (brd, J =2.0 Hz, 1H), 7.96 (brs, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.59 (dd, J =8.6, 2.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 8.8, 2.4 Hz,1H), 4.86 (t, J = 5.1 Hz, 1H), 4.44 (d, J = 3.9 Hz, 1H), 3.30 (d, J =5.0 Hz, 1H), 3.12-2.96 (m, 1H), 1.99 (s, 3H), 1.76- 1.44 (m, 4H). LCMSm/z (M + 1, 420.0) 69

LCMS m/z (M + 1, 377.1) 70

¹H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.46 (d, J = 6.0 Hz, 2H),7.60~7.50 (m, 2H), 7.46~7.35 (m, 2H), 7.29~7.24 (m, 2H), 7.15 (d, J =6.0 Hz, 2H), 4.93 (dd, J = 4.4, 4.4 Hz, 1H), 4.88 (dd, J = 4.4, 4.4 Hz,1H), 3.73 (dd, J = 11.6, 4.8 Hz, 1H), 3.59 (dd, J = 11.6, 5.2 Hz, 1H),2.34~2.27 (m, 1H), 1.71~1.63 (m, 2H). LCMS m/z (M + 1, 425.1) 71

¹H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.53- 8.41 (m, 2H), 8.01 (d, J =2.4 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.8, 2.4 Hz, 1H),7.32-7.21 (m, 2H), 4.93 (t, J = 5.1 Hz, 1H), 4.59 (d, J = 4.4 Hz, 1H),3.40 (d, J = 5.0 Hz, 1H), 3.07 (td, J = 5.2, 1.5 Hz, 1H), 1.79-1.50 (m,4H). LCMS m/z (M + 1, 363.1) 72

¹H NMR (400 MHz, MeOD) δ 8.50-8.44 (m, 2H), 7.66-7.60 (m, 1H), 7.57-7.52(m, 2H), 7.41-7.29 (m, 4H), 7.25-7.19 (m, 1H), 7.15 (ddd, J = 9.9, 8.5,1.3 Hz, 1H), 4.98 (t, J = 5.2 Hz, 1H), 4.63 (d, J = 4.5 Hz, 1H), 3.64(d, J = 5.0 Hz, 1H), 3.12 (td, J = 5.2, 1.7 Hz, 1H), 1.86 (m, 3H), 1.72(m, 1H). LCMS m/z (M + 1, 407.1); 73

¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.24 (s, 1H), 7.83 (d, J = 2.4 Hz,1H), 7.42 (d, J = 8.7 Hz, 1H), 7.36 (s, 1H), 5.65 (s, 1H), 4.88-4.84 (m,1H), 4.60-4.54 (m, 1H), 3.66 (dt, J = 5.7, 3.0 Hz, 2H), 3.16 (t, J = 6.0Hz, 2H), 2.99-2.89 (m, 2H), 2.01 (dddd, J = 7.5, 6.0, 3.9, 2.1 Hz, 2H),1.75-1.69 (m, 2H), 1.61-1.56 (m, 2H), 1.34 (s, 9H). LCMS m/z (M + 1 −Boc, 367.2); 74

¹H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 8.46 (d, J = 6.3 Hz, 2H),7.65-7.20 (m, 11H), 4.86 (m, 1H), 4.78 (m, 1H), 3.66 (dd, J = 11.5, 4.3Hz, 1H), 3.57 (dd, J = 11.4, 5.2 Hz, 1H), 2.04 (t, J = 8.4 Hz, 1H),1.83- 1.73 (m, 1H), 1.66-1.49 (m, 2H). LCMS m/z (M + 1, 371.2); 75

¹H NMR (400 MHz, MeOD) δ 8.61 (dd, J = 4.5, 1.4 Hz, 1H), 8.36-8.32 (m,2H), 7.82 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.5, 2.3 Hz, 1H), 7.62-7.50(m, 1H), 7.49-7.41 (m, 1H), 7.36 (dd, J = 8.5, 2.0 Hz, 1H), 7.24-7.20(m, 2H), 4.70 (d, J = 4.6 Hz, 1H), 4.55 (d, J = 4.7 Hz, 1H), 2.33 (ddd,J = 11.6, 9.0, 4.0 Hz, 1H), 1.94-1.86 (m, 1H), 1.79 (d, J = 4.9 Hz, 1H),1.76- 1.70 (m, 1H), 1.67-1.58 (m, 1H), 1.17 (d, J = 4.8 Hz, 1H). LCMSm/z (M + 1, 460.1); 76

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 8.51 (s, 2H), 7.64 (dd, J =12.0, 2.0 Hz, 1H), 7.59 (s, 2H), 7.53- 7.46 (m, 1H), 7.38-7.30 (m, 4H),7.25 (t, J = 8.3 Hz, 1H), 4.99 (t, J = 5.2 Hz, 1H), 4.64 (d, J = 4.6 Hz,1H), 3.66 (d, J = 4.9 Hz, 1H), 3.13 (td, J = 5.2, 1.7 Hz, 1H), 1.95-1.81(m, 3H), 1.75 (dtd, J = 10.2, 5.0, 1.9 Hz, 1H). LCMS m/z (M + 1, 423.1);77

LCMS m/z (M + 1, 311.1); RT 1.55 min. (Method A) 78

¹H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 2H), 7.38- 7.23 (m, 4H),7.21-7.02 (m, 4H), 4.80 (dd, J = 6.0, 3.6 Hz, 1H), 4.68 (dd, J = 5.8,3.9 Hz, 1H), 3.49 (m, 1H), 3.37 (dd, J = 12.2, 5.0 Hz, 1H), 3.11 (s,6H), 2.51 (ddd, J = 11.8, 8.5, 3.7 Hz, 1H), 1.87 (ddd, J = 12.5, 8.8,3.5 Hz, 1H), 1.72 (dq, J = 29.5, 9.0, 5.7 Hz, 2H). LCMS m/z (M + 1,451.2); 79

¹H NMR (600 MHz, MeOD) δ 8.46-8.43 (m, 2H), 7.62-7.57 (m, 6H), 7.45-7.40(m, 2H), 7.33-7.30 (m, 3H), 4.79 (d, J = 4.7 Hz, 1H), 4.65 (d, J = 4.9Hz, 1H), 2.48 (ddd, J = 11.8, 9.1, 4.2 Hz, 1H), 2.03-1.98 (m, 1H), 1.88(d, J = 4.8 Hz, 1H), 1.87-1.81 (m, 1H), 1.73 (tt, J = 11.7, 4.5 Hz, 1H),1.27-1.25 (m, 1H). LCMS m/z (M + 1, 383.3); 80

LCMS m/z (M + 1, 407.1); RT 1.40 min. (Method A) 81

¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.27 (s, 1H), 7.85 (d, J = 2.5 Hz,1H), 7.44 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 5.69 (dq, J = 2.8, 1.2 Hz,1H), 4.90-4.83 (m, 1H), 4.62-4.57 (m, 1H), 3.95-3.81 (m, 2H), 3.41 (td,J = 5.5, 3.0 Hz, 2H), 2.97 (d, J = 9.6 Hz, 1H), 2.89 (d, J = 9.6 Hz,1H), 2.01 (dq, J = 5.5, 2.6 Hz, 2H), 1.75- 1.69 (m, 2H), 1.62-1.56 (m,2H). LCMS m/z (M + 1, 368.1); 82

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.64 (dd, J = 12.0, 1.9 Hz,1H), 7.45 (s, 1H), 7.42-7.32 (m, 3H), 7.24 (ddd, J = 8.7, 6.7, 1.3 Hz,2H), 7.21-7.14 (m, 1H), 6.48 (s, 1H), 4.91 (t, J = 5.0 Hz, 1H), 4.63 (d,J = 4.9 Hz, 1H), 3.85 (s, 3H), 3.68 (d, J = 4.4 Hz, 1H), 3.03-2.96 (m,1H), 1.92-1.64 (m, 4H). LCMS m/z (M + 1, 478.2); 83

¹H NMR (400 MHz, MeOD) δ 10.13 (s, 1H), 7.95 (t, J = 7.9 Hz, 1H), 7.88(t, J = 1.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H),7.53 (dt, J = 8.5, 1.7 Hz, 1H), 7.43 (s, 1H), 7.42-7.40 (m, 3H),7.40-7.34 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.98 (t, J = 5.2 Hz, 1H),4.81 (t, J = 2.7 Hz, 1H), 3.81 (d, J = 5.1 Hz, 1H), 3.72-3.67 (m, 1H),2.00-1.86 (m, 3H), 1.74 (tdd, J = 9.2, 4.6, 1.7 Hz, 1H). LCMS m/z (M +1, 473.1); 84

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.88 (s, 1H), 7.40-7.30 (m,2H), 7.25-7.11 (m, 4H), 6.88 (dd, J = 8.3, 2.1 Hz, 1H), 6.54 (s, 1H),5.02 (d, J = 4.2 Hz, 1H), 4.97-4.94 (m, 1H), 3.83 (s, 3H), 3.53 (d, J =9.1 Hz, 1H), 3.21 (d, J = 9.2 Hz, 1H), 1.96 (dtd, J = 8.0, 4.5, 3.7, 1.9Hz, 2H), 1.80-1.70 (m, 2H). LCMS m/z (M + 1, 478.2); 85

¹H NMR (400 MHz, MeOD) δ 8.47-8.43 (m, 2H), 7.70-7.17 (m, 9H), 4.79 (d,J = 4.7 Hz, 1H), 4.65 (d, J = 4.8 Hz, 1H), 2.45 (ddd, J = 11.5, 9.1, 4.0Hz, 1H), 2.04-1.96 (m, 1H), 1.88 (d, J = 4.9 Hz, 1H), 1.83 (dt, J =11.3, 4.4 Hz, 1H), 1.79-1.69 (m, 1H), 1.26 (d, J = 4.8 Hz, 1H). LCMS m/z(M + 1, 435.2); 86

¹H NMR (400 MHz, MeOD) δ 10.07 (s, 1H), 7.93 (t, J = 7.9 Hz, 1H),7.70-7.59 (m, 3H), 7.43-7.31 (m, 4H), 7.24 (td, J = 7.5, 1.3 Hz, 1H),7.20-7.13 (m, 1H), 4.97 (t, J = 5.2 Hz, 1H), 4.83 (d, J = 4.0 Hz, 1H),3.78 (d, J = 5.3 Hz, 1H), 3.65 (td, J = 5.3, 1.6 Hz, 1H), 2.04-1.95 (m,1H), 1.92-1.84 (m, 2H), 1.79-1.70 (m, 1H). LCMS m/z (M + 1, 475.1); 87

¹H NMR (400 MHz, Chloroform-d) δ 7.58-7.01 (m, 8H), 6.97 (d, J = 3.3 Hz,2H), 4.80 (q, J = 5.2 Hz, 2H), 3.49 (qd, J = 11.3, 4.6 Hz, 2H), 2.18(ddd, J = 12.1, 8.7, 3.0 Hz, 1H), 1.99 (ddd, J = 16.5, 7.9, 4.2 Hz, 1H),1.84-1.62 (m, 2H). LCMS m/z (M + 1, 475.0); 88

¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.57 (s, 1H), 7.97-7.90 (m, 1H),7.47-7.43 (m, 2H), 5.49 (s, 1H), 4.76 (t, J = 5.0 Hz, 1H), 4.47 (d, J =4.9 Hz, 1H), 3.83 (dd, J = 5.5, 3.0 Hz, 2H), 3.51 (dt, J = 13.1, 5.6 Hz,1H), 3.45-3.35 (m, 1H), 2.93-2.83 (m, 2H), 2.08 (ddt, J = 5.8, 4.0, 2.2Hz, 2H), 1.77-1.66 (m, 2H), 1.63-1.52 (m, 2H), 1.44 (s, 9H). LCMS m/z(M + 1 − Boc, 367.2); 89

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.84 (d, J = 2.4 Hz, 1H), 7.40(d, J = 8.7 Hz, 1H), 7.38 (s, 1H), 7.29 (dd, J = 8.8, 2.5 Hz, 1H), 6.46(s, 1H), 4.88 (t, J = 5.1 Hz, 1H), 4.62 (d, J = 4.9 Hz, 1H), 3.83 (s,3H), 3.65 (d, J = 4.4 Hz, 1H), 2.96 (td, J = 5.1, 1.6 Hz, 1H), 1.92-1.66(m, 4H). LCMS m/z (M + 1, 434.1); 90

¹H NMR (400 MHz, MeOD) δ 8.47-8.43 (m, 2H), 7.81 (d, J = 2.1 Hz, 1H),7.69-7.16 (m, 9H), 4.79 (d, J = 4.6 Hz, 1H), 4.64 (d, J = 4.7 Hz, 1H),2.45 (ddd, J = 11.5, 9.3, 4.2 Hz, 1H), 2.03-1.96 (m, 1H), 1.88 (d, J =4.8 Hz, 1H), 1.83 (dt, J = 11.5, 4.4 Hz, 1H), 1.77- 1.70 (m, 1H), 1.26(d, J = 4.9 Hz, 1H). LCMS m/z (M + 1, 417.2); 91

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 9.51 (s, 1H), 7.81 (d, J = 5.7Hz, 1H), 7.67-7.62 (m, 1H), 7.42-7.30 (m, 4H), 7.26-7.21 (m, 1H), 7.17(ddd, J = 10.0, 8.7, 1.2 Hz, 1H), 6.68 (dd, J = 5.7, 1.5 Hz, 1H), 6.57(d, J = 1.3 Hz, 1H), 5.40 (br s, 2H), 4.89 (t, J = 5.2 Hz, 1H), 4.60 (d,J = 4.7 Hz, 1H), 3.41 (d, J = 5.1 Hz, 1H), 3.05 (td, J = 5.2, 1.6 Hz,1H), 1.92-1.64 (m, 4H). LCMS m/z (M + 1, 422.2); 92

¹H NMR (400 MHz, MeOD) δ 10.15 (s, 1H), 7.97- 7.91 (m, 2H), 7.62 (t, J =8.4 Hz, 2H), 7.47-7.38 (m, 2H), 4.95 (t, J = 5.2 Hz, 1H), 4.81-4.77 (m,1H), 3.78 (d, J = 5.2 Hz, 1H), 3.70-3.64 (m, 1H), 1.94-1.84 (m, 3H),1.72 (ddd, J = 10.1, 5.1, 1.8 Hz, 1H). LCMS m/z (M + 1, 431.1); 93

¹H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 8.51- 8.47 (m, 2H), 8.47-8.40(m, 1H), 7.51-7.04 (m, 8H), 3.52 (dd, J = 12.7, 1.8 Hz, 1H), 3.25 (ddd,J = 12.6, 5.8, 2.2 Hz, 1H), 1.83 (ddd, J = 13.1, 9.2, 4.3 Hz, 1H), 1.73(ddd, J = 12.8, 9.2, 4.1 Hz, 1H), 1.65-1.53 (m, 2H), 1.46 (s, 3H), 1.29(s, 3H). LCMS m/z (M + 1, 435.2); 94

LCMS m/z (M + 1, 367.1); RT 1.27 min. (Method A) 95

¹H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 5.3 Hz, 1H), 7.32 (dd, J =11.7, 1.9 Hz, 1H), 7.29-7.02 (m, 8H), 4.85 (t, J = 5.1 Hz, 2H), 3.73(dd, J = 10.7, 5.9 Hz, 1H), 3.58-3.52 (m, 1H), 2.24-2.15 (m, 1H), 1.88(td, J = 10.8, 3.2 Hz, 2H), 1.67 (dq, J = 12.5, 6.8, 6.0 Hz, 1H). LCMSm/z (M + 1, 459.1); 96

¹H NMR (400 MHz, MeOD) δ 8.47-8.42 (m, 2H), 7.84 (d, J = 2.2 Hz, 1H),7.71-6.96 (m, 8H), 4.79 (d, J = 4.7 Hz, 1H), 4.65 (d, J = 4.9 Hz, 1H),2.45 (ddd, J = 11.6, 9.1, 4.1 Hz, 1H), 2.06-1.97 (m, 1H), 1.88 (d, J =4.8 Hz, 1H), 1.84 (td, J = 7.6, 3.9 Hz, 1H), 1.72 (tt, J = 11.8, 4.6 Hz,1H), 1.26 (d, J = 4.8 Hz, 1H). LCMS m/z (M + 1, 435.2); 97

¹H NMR (400 MHz, MeOD) δ 8.11 (d, J = 5.1 Hz, 1H), 7.54 (d, J = 12.4 Hz,1H), 7.43-7.12 (m, 7H), 5.50 (dd, J = 4.4, 0.9 Hz, 1H), 5.39-5.37 (m,1H), 2.14- 1.97 (m, 2H), 1.76 (ddd, J = 10.9, 8.8, 3.0 Hz, 1H), 1.56(ddd, J = 11.8, 8.7, 3.1 Hz, 1H). LCMS m/z (M + 1, 457.0); 98

¹H NMR (400 MHz, MeOD) δ 10.45 (s, 1H), 9.12- 9.04 (m, 2H), 8.48 (t, J =1.9 Hz, 1H), 8.14-8.04 (m, 6H), 8.04-7.97 (m, 1H), 7.92 (d J = 8.4 Hz,1H), 5.59 (t, J = 5.2 Hz, 1H), 5.26 (d, J = 4.6 Hz, 1H), 4.22 (d, J =4.9 Hz, 1H), 3.74 (td, J = 5.2, 1.6 Hz, 1H), 2.58- 2.30 (m, 4H). LCMSm/z (M + 1, 405.1); 99

¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.55 (s, 1H), 8.29 (d, J = 5.3 Hz,1H), 7.92 (d, J = 2.3 Hz, 1H), 7.49- 7.40 (m, 2H), 7.35 (d, J = 1.6 Hz,1H), 7.31-7.24 (m, 1H), 4.94 (t, J = 5.1 Hz, 1H), 4.59 (d, J = 4.9 Hz,1H), 3.51 (d, J = 4.9 Hz, 1H), 3.05 (td, J = 5.2, 1.7 Hz, 1H), 1.84-1.62(m, 4H). LCMS m/z (M + 1, 397.1); 100

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.80 (d, J = 2.1 Hz, 1H),7.46-7.35 (m, 7H), 7.31 (d, J = 8.2 Hz, 1H), 6.48 (s, 1H), 4.91 (t, J =5.1 Hz, 1H), 4.63 (d, J = 4.9 Hz, 1H), 3.84 (s, 3H), 3.68 (d, J = 4.5Hz, 1H), 3.00 (td, J = 5.2, 1.6 Hz, 1H), 1.93-1.68 (m, 4H). LCMS m/z(M + 1, 476.2); 101

¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.62 (s, 1H), 7.70-7.62 (m, 1H),7.51-7.36 (m, 4H), 7.34-7.21 (m, 2H), 5.01 (d, J = 4.5 Hz, 1H),4.88-4.83 (m, 1H), 3.40 (d, J = 9.4 Hz, 1H), 3.07 (d, J = 9.4 Hz, 1H),1.84- 1.56 (m, 4H). LCMS m/z (M + 1, 355.2); 102

¹H NMR (400 MHz, MeOD) δ 8.68 (d, J = 4.9 Hz, 2H), 7.80-7.73 (m, 2H),7.67 (td, J = 8.4, 6.3 Hz, 1H), 7.50 (t, J = 8.3 Hz, 1H), 7.45 (dd, J =12.2, 2.1 Hz, 1H), 7.38-7.26 (m, 2H), 7.24 (dd, J = 8.4, 2.1 Hz, 1H),5.41 (d, J = 4.3 Hz, 1H), 5.08 (d, J = 4.3 Hz, 1H), 3.88 (d, J = 9.7 Hz,1H), 3.61 (d, J = 9.7 Hz, 1H), 2.33- 2.20 (m, 2H), 2.15-2.03 (m, 2H).LCMS m/z (M + 1, 425.1); 103

¹H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.48 (dd, J = 4.4, 1.6 Hz, 2H),8.01 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.8,2.4 Hz, 1H), 7.27 (dd, J = 4.5, 1.7 Hz, 2H), 4.93 (t, J = 5.1 Hz, 1H),4.59 (d, J = 4.3 Hz, 1H), 3.39 (d, J = 5.0 Hz, 1H), 3.07 (td, J = 5.1,1.5 Hz, 1H), 1.80-1.49 (m, 4H). LCMS m/z (M + 1, 363.1); 104

¹H NMR (400 MHz, MeOD) δ 8.71 (d, J = 5.3 Hz, 2H), 7.84 (d, J = 5.3 Hz,2H), 7.78-7.67 (m, 5H), 7.64 (d, J = 2.2 Hz, 1H), 7.49 (d J = 8.4 Hz,1H), 7.36 (dd, J = 8.3, 2.2 Hz, 1H), 5.41 (d, J = 4.3 Hz, 1H), 5.08 (d,J = 4.3 Hz, 1H), 3.90 (d, J = 9.7 Hz, 1H), 3.62 (d, J = 9.7 Hz, 1H),2.29-2.22 (m, 2H), 2.16-2.03 (m, 2H). LCMS m/z (M + 1, 405.1); 105

¹H NMR (400 MHz, MeOD) δ 8.45 (s, 2H), 7.99-7.94 (m, 2H), 7.73-7.65 (m,2H), 7.42 (d, J = 5.1 Hz, 2H), 4.96 (t, J = 5.2 Hz, 1H), 4.64 (d, J =4.5 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.55 (d, J = 5.0 Hz, 1H), 3.14(td, J = 5.3, 1.6 Hz, 1H), 1.92-1.78 (m, 3H), 1.70 (dtd, J = 13.7, 5.0,2.9 Hz, 1H), 1.38 (t, J = 7.1 Hz, 3H). LCMS m/z (M + 1, 367.2); 106

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 8.14 (s, 1H), 7.83 (d, J = 2.2Hz, 1H), 7.77 (d, J = 5.7 Hz, 1H), 7.46-7.35 (m, 6H), 7.29 (d, J = 8.3Hz, 1H), 6.66 (dd, J = 5.8, 1.5 Hz, 1H), 6.58-6.54 (m, 1H), 5.73-5.36(br s, 2H), 4.84 (t, J = 5.1 Hz, 1H), 4.60 (d, J = 5.0 Hz, 1H), 3.38 (d,J = 5.0 Hz, 1H), 2.96 (td, J = 5.1, 1.6 Hz, 1H), 1.99-1.65 (m, 4H). LCMSm/z (M + 1, 420.2); 107

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 8.11 (s, 1H), 7.90-7.83 (m,2H), 7.39-7.33 (m, 2H), 6.59 (dd, J = 5.4, 1.5 Hz, 1H), 6.45 (d, J = 1.4Hz, 1H), 4.76 (t, J = 5.1 Hz, 1H), 4.59 (d, J = 5.0 Hz, 1H), 4.55 (br s,2H), 3.29 (d, J = 5.0 Hz, 1H), 2.88 (td, J = 5.2, 1.7 Hz, 1H), 1.97-1.49(m, 4H). LCMS m/z (M + 1, 378.1); 108

¹H NMR (400 MHz, MeOD) δ 8.48-8.40 (m, 2H), 7.86 (d, J = 1.9 Hz, 1H),7.45 (d, J = 2.3 Hz, 2H), 7.32- 7.27 (m, 2H), 4.76 (d, J = 4.7 Hz, 1H),4.63 (d, J = 4.8 Hz, 1H), 2.41 (ddd, J = 11.5, 9.1, 4.1 Hz, 1H), 2.02-1.95 (m, 1H), 1.85 (s, 1H), 1.81 (dt, J = 11.5, 4.3 Hz, 1H), 1.77-1.66(m, 1H), 1.22 (d, J = 4.8 Hz, 1H). LCMS m/z (M + 1, 375.1); 109

¹H NMR (400 MHz, MeOD) δ 8.53 (d, J = 3.1 Hz, 1H), 8.40 (d, J = 5.8 Hz,1H), 7.59 (d, J = 11.6 Hz, 1H), 7.52-7.45 (m, 1H), 7.42-7.29 (m, 4H),7.24 (t, J = 7.5 Hz, 1H), 7.21-7.12 (m, 1H), 5.47 (d, J = 4.2 Hz, 1H),5.40 (d, J = 5.4 Hz, 1H), 2.05 (td, J = 13.8, 11.0, 6.7 Hz, 2H),1.73-1.63 (m, 1H), 1.60 (t, J = 8.4 Hz, 1H). LCMS m/z (M + 1, 423.0);110

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 9.32 (s, 1H), 7.53 (t, J = 1.8Hz, 1H), 7.50-7.30 (m, 6H), 7.23- 7.16 (m, 2H), 7.10 (s 1H), 6.93 (s1H), 5.04 (d J = 4.0 Hz, 1H), 4.63 (d, J = 4.0 Hz, 1H), 3.56 (d, J = 9.5Hz, 1H), 3.33 (d, J = 8.8 Hz, 1H), 1.94-1.66 (m, 4H). LCMS m/z (M + 1,420.2); 111

¹H NMR (400 MHz, MeOD) δ 10.35 (s, 1H), 8.83- 8.73 (m, 2H), 7.99 (dt, J= 12.4, 1.7 Hz, 1H), 7.79- 7.75 (m, 2H), 7.75-7.61 (m, 3H), 7.38-7.26(m, 2H), 5.31 (t, J = 5.2 Hz, 1H), 4.97 (d, J = 4.6 Hz, 1H), 3.92 (d, J= 5.0 Hz, 1H), 3.47 (td, J = 5.3, 1.6 Hz, 1H), 2.27-2.14 (m, 3H), 2.07(tdd, J = 10.5, 5.1, 1.9 Hz, 1H). LCMS m/z (M + 1, 425.1); 112

¹H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 7.50 (dd, J = 12.0, 2.0Hz, 1H), 7.33-7.23 (m, 3H), 7.21- 7.06 (m, 3H), 5.01-4.96 (m, 1H),4.89-4.85 (m, 1H), 3.11-3.04 (m, 1H), 2.99 (d, J = 9.8 Hz, 1H),1.91-1.76 (m, 2H), 1.62-1.49 (m, 2H). LCMS m/z (M + 23, 395.2); 113

¹H NMR (600 MHz, MeOD) δ 8.46-8.41 (m, 2H), 7.59 (dd, J = 12.3, 2.0 Hz,1H), 7.46-7.36 (m, 5H), 7.35 (t, J = 8.2 Hz, 1H), 7.28-7.24 (m, 1H),7.19 (ddd, J = 9.6, 8.3, 1.1 Hz, 1H), 4.79 (d, J = 4.7 Hz, 1H), 4.66 (d,J = 4.8 Hz, 1H), 2.45 (ddd, J = 11.8, 9.1, 4.1 Hz, 1H), 2.01 (ddd, J =12.8, 9.1, 4.0 Hz, 1H), 1.88 (d, J = 4.8 Hz, 1H), 1.85 (ddd, J = 11.8,7.4, 4.5 Hz, 1H), 1.77-1.71 (m, 1H), 1.27 (d, J = 4.8 Hz, 1H). LCMS m/z(M + 1, 419.2); 114

¹H NMR (400 MHz, MeOD) δ 8.47-8.44 (m, 2H), 8.11 (d, J = 2.2 Hz, 1H),7.88 (dd, J = 8.5, 2.3 Hz, 1H), 7.59-7.55 (m, 1H), 7.47-7.38 (m, 4H),7.34-7.30 (m, 2H), 4.81 (d, J = 4.6 Hz, 1H), 4.65 (d, J = 4.7 Hz, 1H),2.45 (ddd, J = 11.7, 9.1, 4.1 Hz, 1H), 2.01 (ddd, J = 12.7, 9.2, 4.0 Hz,1H), 1.89 (d, J = 4.9 Hz, 1H), 1.88- 1.81 (m, 1H), 1.78-1.69 (m, 1H),1.28 (d, J = 5.0 Hz, 1H). LCMS m/z (M + 1, 442.2); 115

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.62 (s, 1H), 7.49-7.04 (m,5H), 6.93 (s, 1H), 5.02 (d, J = 3.4 Hz, 1H), 4.62 (d, J = 3.5 Hz, 1H),3.58 (m, 1H), 3.34 (m, 1H), 1.92-1.82 (m, 2H), 1.72 (m, 2H). LCMS m/z(M + 1, 378.1); 116

¹H NMR (400 MHz, MeOD) δ 7.64 (d, J = 12.0 Hz, 1H), 7.45-7.35 (m, 6H),7.28-7.22 (m, 1H), 7.18 (dd, J = 10.3, 8.2 Hz, 1H), 5.45 (d, J = 3.8 Hz,1H), 5.39-5.37 (m, 1H), 2.08 (dq, J = 9.5, 5.1, 4.0 Hz, 2H), 1.71 (t, J= 8.3 Hz, 1H), 1.51 (dd, J = 9.2, 7.7 Hz, 1H). LCMS m/z (M + 1, 473.0);117

¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.60 (s, 1H), 7.94-7.90 (m, 1H),7.45 (d, J = 1.8 Hz, 2H), 5.54 (tt, J = 2.7, 1.3 Hz, 1H), 4.76 (t, J =5.0 Hz, 1H), 4.50 (d, J = 5.0 Hz, 1H), 4.05 (q, J = 2.6, 1.8 Hz, 2H),3.78- 3.66 (m, 2H), 2.92 (td, J = 5.2, 1.6 Hz, 1H), 2.83 (d, J = 5.2 Hz,1H), 2.10-2.02 (m, 2H), 1.72 (dtt, J = 10.2, 7.6, 5.3 Hz, 2H), 1.63-1.50(m, 2H). LCMS m/z (M + 1, 368.1); 118

¹H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.48 (dd, J = 4.4, 1.6 Hz, 2H),8.01 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.8,2.4 Hz, 1H), 7.27 (dd, J = 4.5, 1.7 Hz, 2H), 4.93 (t, J = 5.1 Hz, 1H),4.59 (d, J = 4.3 Hz, 1H), 3.39 (d, J = 5.0 Hz, 1H), 3.07 (td, J = 5.1,1.5 Hz, 1H), 1.80-1.49 (m, 4H). LCMS m/z (M + 1, 363.1); 119

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.87- 7.82 (m, 2H), 7.41-7.37(m, 3H), 7.10 (d, J = 1.5 Hz, 1H), 6.92-6.89 (m, 1H), 5.04 (d, J = 4.2Hz, 1H), 4.62 (d, J = 4.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.55 (d, J= 1.4 Hz, 1H), 3.35-3.28 (m, 1H), 1.87 (td, J = 5.5, 4.7, 3.1 Hz, 2H),1.77-1.67 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H). LCMS m/z (M + 1, 382.2);120

¹H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 8.53- 8.42 (m, 2H), 7.69-7.60(m, 6H), 7.44 (dd, J = 8.4, 7.0 Hz, 2H), 7.35-7.27 (m, 3H), 4.95 (t, J =5.1 Hz, 1H), 4.59 (d, J = 3.9 Hz, 1H), 3.43 (d, J = 5.0 Hz, 1H), 3.10(td, J = 5.2, 1.5 Hz, 1H), 1.77-1.67 (m, 3H), 1.63-1.54 (m, 1H). LCMSm/z (M + 1, 371.3); 121

LCMS m/z (M + 1, 371.1); 122

LCMS m/z (M + 1, 374.1); 123

LCMS m/z (M + 1, 491.1); 124

LCMS m/z (M + 1, 316.1) 125

¹H NMR (400 MHz, CDCl₃) δ 8.47 (t, J = 7.3, 1H), 7.69 (s, 1H), 7.36 (dd,J = 3.8, 10.6, 1H), 7.26 (dt, J = 4.2, 10.2, 1H), 4.76 (dt, J = 5.0,16.1, 2H), 3.33 (t, J = 10.1, 1H), 3.20 (d, J = 6.9, 1H), 3.03 (dd, J =5.1, 10.5, 1H), 2.25 (ddd, J = 6.4, 11.0, 12.2, 2H), 1.99 (ddd, J = 5.1,9.2, 12.0, 1H), 1.87 (d, J = 9.7, 2H), 1.72-1.55 (m, 3H), 1.52-1.35 (m,2H), 1.15 (d, J = 11.3, 1H). LCMS m/z (M + 1, 455.1) 126

¹H NMR (400 MHz, MeOD) δ 7.97 (d, J = 8.8, 2H), 7.80-7.63 (m, 2H), 6.64(s, 1H), 4.93 (t, J = 4.8, 1H), 4.81 (d, J = 5.0, 1H), 4.34 (q, J = 7.1,2H), 4.04 (t, J = 5.2, 1H), 3.96 (s, 3H), 2.99 (d, J = 5.7, 1H), 1.95-1.72 (m, 2H), 1.64-1.51 (m, 2H), 1.38 (t, J = 7.1, 3H). LCMS m/z (M + 1,438.1) 127

LCMS m/z (M + 1, 367.1) 128

LCMS m/z (M + 1, 411.1) 129

¹H NMR (400 MHz, CDCl₃) δ 11.65 (s, 1H), 8.15- 7.95 (m, 3H), 7.82-7.68(m, 3H), 7.60 (d, J = 8.0, 1H), 5.68-5.63 (m, 1H), 5.50 (dd, J = 1.1,4.3, 1H), 4.38 (dt, J = 5.5, 7.1, 2H), 2.22-2.14 (m, 2H), 1.75 (dd, J =8.0, 8.8, 1H), 1.68-1.61 (m, 1H), 1.44-1.36 (m, 3H). LCMS m/z (M + 1,433.1) 130

¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 7.52-7.40 (m, 1H), 7.40-7.32 (m,1H), 7.26-7.20 (m, 1H), 6.66 (s, 1H), 5.54 (d, J = 4.5, 1H), 5.28 (d, J= 4.0, 1H), 3.96 (s, 3H), 2.24-2.01 (m, 2H), 1.70-1.63 (m, 1H), 1.48(ddd, J = 3.0, 8.8, 11.9, 1H). LCMS m/z (M + 1, 450.1) 131

LCMS m/z (M + 1, 380.1) 132

LCMS m/z (M + 1, 387.1) 133

LCMS m/z (M + 1, 379.1) 134

¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.78 (t, J = 1.3, 1H), 7.40 (d,J = 1.4, 2H), 6.49 (s, 1H), 4.91 (dd, J = 5.2, 10.9, 2H), 3.93 (s, 3H),3.78-3.65 (m, 1H), 2.83 (d, J = 5.2, 1H), 2.06-1.91 (m, 1H), 1.74-1.61(m, 3H). LCMS m/z (M + 1, 438.1) 135

¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1H), 8.22 (s, 1H), 7.61 (d, J = 2.3,1H), 7.40-7.32 (m, 1H), 7.26 (s, 1H), 7.20-7.03 (m, 3H), 4.92 (t, J =4.4, 1H), 4.86 (t, J = 4.8, 1H), 3.76-3.62 (m, 1H), 3.62-3.51 (m, 1H),2.48-2.32 (m, 1H), 2.02-1.94 (m, 1H), 1.90-1.70 (m, 2H). LCMS m/z (M +1, 363.0) 136

¹H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 8.17 (t, J = 7.9, 1H), 8.02-7.90(m, 2H), 7.87 (dd, J = 0.5, 7.8, 1H), 7.60 (d, J = 8.8, 1H), 7.54 (dd, J= 2.3, 8.8, 1H), 5.71 (d, J = 3.3, 1H), 5.41 (d, J = 3.2, 1H), 2.03-1.85(m, 2H), 1.60 (t, J = 8.3, 1H), 1.43 (t, J = 8.3, 1H). LCMS m/z (M + 1,429.0) 137

¹H NMR (400 MHz, CDCl₃) δ 7.61-7.47 (m, 1H), 7.43-7.30 (m, 3H),7.25-7.11 (m, 3H), 7.00 (d, J = 7.6, 1H), 6.69 (s, 1H), 5.54 (d, J =4.2, 1H), 5.30 (d, J = 4.4, 1H), 3.94 (s, 3H), 2.21-2.05 (m, 2H), 1.78-1.63 (m, 1H), 1.53-1.39 (m, 1H). LCMS m/z (M + 1, 476.1) 138

LCMS m/z (M + 1, 371.1) 139

LCMS m/z (M + 1, 379.1) 140

LCMS m/z (M + 1, 364.0) 141

¹H NMR (400 MHz, CDCl₃) δ 7.69 (s, 1H), 7.38 (d, J = 8.7, 1H), 7.18-7.02(m, 2H), 6.65 (s, 1H), 5.50 (d, J = 3.9, 1H), 5.28 (d, J = 4.4, 1H),3.93 (s, 3H), 2.22- 2.07 (m, 2H), 1.76-1.61 (m, 1H), 1.48-1.37 (m, 1H).LCMS m/z (M + 1, 432.0) 142

LCMS m/z (M + 1, 436.1) 143

LCMS m/z (M + 1, 475.1) 144

¹H NMR (400 MHz, CDCl₃) δ 8.80 (d, J = 2.3, 1H), 8.74 (d, J = 2.4, 2H),7.94 (d, J = 2.4, 1H), 7.52 (dd, J = 2.4, 8.7, 1H), 7.42 (d, J = 8.7,1H), 5.68 (dd, J = 1.0, 4.3, 1H), 5.65-5.56 (m, 1H), 2.29-2.07 (m, 2H),1.75-1.63 (m, 2H). LCMS m/z (M + 1, 362.0) 145

¹H NMR (400 MHz, CDCl₃) δ 8.52 (dd, J = 1.6, 4.5, 2H), 8.46-8.34 (m,1H), 7.32 (dddd, J = 0.7, 1.4, 2.0, 3.4, 1H), 7.30-7.27 (m, 2H),7.08-6.97 (m, 2H), 4.91 (t, J = 5.0, 1H), 4.65 (d, J = 4.9, 1H), 3.47(d, J = 5.0, 1H), 3.02 (td, J = 1.6, 5.2, 1H), 2.00-1.70 (m, 4H). LCMSm/z (M + 1, 347.1) 146

LCMS m/z (M + 1, 344.1) 147

LCMS m/z (M + 1, 347.1) 148

LCMS m/z (M + 1, 354.1) 149

¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 8.62 (s, 2H), 7.96 (d, J = 8.8,2H), 7.87 (dd, J = 7.2, 8.6, 3H), 7.64 (d, J = 8.7, 2H), 5.06 (t, J =5.0, 1H), 4.66 (d, J = 4.7, 1H), 4.37 (q, J = 7.1, 2H), 3.83 (d, J =4.6, 1H), 3.20 (t, J = 4.5, 1H), 2.04-1.74 (m, 4H), 1.41 (t, J = 7.1,3H). LCMS m/z (M + 1, 367.1) 150

LCMS m/z (M + 1, 473.1) 151

LCMS m/z (M + 1, 397.2) 152

¹H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H),7.56-7.45 (m, 1H), 7.44-7.19 (m, 6H), 6.34 (s, 1H), 4.78 (dt, J = 4.8,10.0 Hz, 2H), 3.61 (dd, J = 4.8, 11.3 Hz, 1H), 3.45 (dd, J = 5.2, 11.4Hz, 1H), 2.15-2.01 (m, 1H), 1.97-1.83 (m, 1H), 1.54 (dt, J = 6.8, 11.6Hz, 2H). LCMS m/z (M + 1, 476.1) 153

¹H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.42(t, J = 6.8 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.29 (s, 1H), 4.77 (dt, J= 4.6, 11.8 Hz, 2H), 3.73 (s, 3H), 3.66 (dd, J = 4.7, 11.6 Hz, 1H), 3.55(dd, J = 4.9, 11.6 Hz, 1H), 2.15 (t, J = 8.6 Hz, 1H), 1.84 (t, J = 8.3Hz, 1H), 1.53 (dd, J = 4.9, 7.9 Hz, 2H). LCMS m/z (M + 1, 452.1) 154

LCMS m/z (M + 1, 411.1) 155

¹H NMR (400 MHz, CDCl₃) δ 7.80 (t, J = 7.8, 1H), 7.51 (t, J = 9.7, 2H),7.35-7.27 (m, 3H), 7.11 (dd, J = 2.3, 8.7, 1H), 4.98-4.86 (m, 2H), 3.92(dd, J = 4.5, 11.3, 1H), 3.52 (dd, J = 5.1, 11.4, 1H), 2.39 (t, J = 8.6,1H), 1.99 (t, J = 8.4, 1H), 1.78 (dd, J = 4.6, 8.0, 2H). LCMS m/z (M +1, 431.1) 156

¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J = 2.3, 1H), 7.36 (d, J = 8.7, 1H),7.13 (dd, J = 2.3, 8.7, 1H), 6.97 (s, 1H), 6.49 (s, 1H), 4.95 (t, J =4.5, 1H), 4.83 (t, J = 4.5, 1H), 3.83 (s, 3H), 3.63 (dd, J = 4.5, 11.3,1H), 3.39 (dd, J = 4.9, 11.1, 1H), 2.35 (t, J = 8.9, 1H), 2.11 (t, J =8.4, 1H), 1.92- 1.68 (m, 2H). LCMS m/z (M + 1, 343.0) 157

¹H NMR (400 MHz, CDCl₃) δ 11.91 (s, 1H), 8.10 (t, J = 7.8, 2H),7.84-7.68 (m, 1H), 7.62 (d, J = 8.0, 1H), 7.43 (dd, J = 3.8, 10.2, 1H),7.28-7.17 (m, 1H), 5.77- 5.61 (m, 1H), 5.55 (dd, J = 1.5, 3.1, 1H),2.26-2.08 (m, 2H), 1.72 (m, 1H), 1.62-1.54 (m, 1H). LCMS m/z (M + 1,447.0) 158

¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 8.7, 2H), 7.32 (d, J = 8.3, 2H),7.13 (d, J = 0.6, 1H), 6.42 (s, 1H), 4.87 (t, 1H), 4.75 (t, 1H), 4.28(q, J = 7.1, 2H), 3.72 (s, 3H), 3.60-3.48 (m, 1H), 3.41-3.28 (m, 1H),2.29 (t, J = 8.9, 1H), 2.06-1.96 (m, 1H), 1.73 (m, 2H), 1.31 (t, J =7.1, 3H). LCMS m/z (M + 1, 438.1) 159

¹H NMR (400 MHz, MeOD) δ 8.31 (dd, J = 1.5, 4.7, 2H), 7.26 (dd, J = 1.5,4.7, 2H), 4.69 (t, J = 5.2, 1H), 4.46 (d, J = 4.7, 1H), 3.60-3.47 (m,1H), 3.34 (d, J = 5.0, 1H), 2.79 (td, J = 1.6, 5.2, 1H), 1.78-1.59 (m,7H), 1.57- 1.47 (m, J = 2.6, 4.9, 8.6, 2H), 1.34-1.16 (m, 2H), 1.16-0.98(m, J = 2.9, 11.0, 11.9, 3H). LCMS m/z (M + 1, 301.1) 160

¹H NMR (400 MHz, CDCl₃) δ 11.70 (s, 1H), 8.09 (d, J = 8.0, 1H), 7.89 (d,J = 2.1, 1H), 7.82-7.73 (m, 1H), 7.67-7.53 (m, 2H), 7.51-7.39 (m, 5H),7.35 (d, J = 8.4, 1H), 5.76-5.59 (m, 1H), 5.59-5.44 (m, 1H), 2.28-2.11(m, 2H), 1.76 (t, J = 8.4, 1H), 1.65 (d, J = 8.8, 1H). LCMS m/z (M + 1,471.1) 161

¹H NMR (400 MHz, MeOD) δ 8.33 (d, J = 6.1, 2H), 8.08 (s, 1H), 8.02 (s,1H), 7.35-7.24 (m, 2H), 4.87 (t, J = 5.2, 1H), 4.52 (d, J = 4.6, 1H),3.46 (d, J = 4.9, 1H), 3.09 (t, J = 4.5, 1H), 2.30 (s, 3H), 1.80-1.65(m, 3H), 1.65-1.50 (m, 1H). LCMS m/z (M + 1, 344.1) 162

LCMS m/z (M + 1, 363.0) 163

¹H NMR (400 MHz, MeOD) δ 8.34 (d, J = 6.0, 2H), 7.40-7.27 (m, 2H), 7.24(dd, J = 1.5, 8.0, 1H), 6.67 (t, J = 8.2, 1H), 6.56 (dd, J = 1.5, 8.3,1H), 4.85 (d, J = 5.2, 1H), 4.51 (d, J = 4.8, 1H), 4.23-4.06 (m, 4H),3.42 (d, J = 5.0, 1H), 3.13 (td, J = 1.4, 5.2, 1H), 1.88-1.79 (m, 1H),1.79-1.50 (m, 3H). LCMS m/z (M + 1, 353.1) 164

LCMS m/z (M + 1, 406.1) 165

LCMS m/z (M + 1, 347.1) 166

¹H NMR (400 MHz, DMSO) δ 9.83 (s, 1H), 8.15 (d, J = 4.8 Hz, 1H),7.43-7.25 (m, 3H), 7.27-7.13 (m, 3H), 7.08 (dd, J = 1.9, 8.4 Hz, 1H),6.91 (d, J = 21.3 Hz, 2H), 4.76 (t, J = 4.5 Hz, 1H), 4.69 (t, J = 4.0Hz, 1H), 3.69 (dd, J = 4.9, 11.6 Hz, 1H), 3.38 (dd, J = 4.8, 11.4 Hz,1H), 2.33-2.10 (m, 4H), 1.80 (t, J = 8.1 Hz, 1H), 1.55-1.35 (m, 2H).LCMS m/z (M + 1, 421.1) 167

LCMS m/z (M + 1, 490.2) 168

LCMS m/z (M + 1, 382.1) 169

LCMS m/z (M + 1, 397.1) 170

LCMS m/z (M + 1, 330.1) 171

LCMS m/z (M + 1, 421.2) 172

LCMS m/z (M + 1, 397.1) 173

LCMS m/z (M + 1, 478.1) 174

¹H NMR (400 MHz, MeOD) δ 8.34 (dd, J = 1.5, 4.7, 2H), 8.20-8.02 (m, 2H),7.31 (dd, J = 1.3, 4.8, 2H), 7.11-6.95 (m, 1H), 4.88 (t, J = 5.2, 1H),4.52 (d, J = 4.6, 1H), 3.47 (d, J = 4.9, 1H), 3.11 (dd, J = 3.1, 7.0,1H), 1.82-1.67 (m, 3H), 1.64-1.52 (m, 1H). LCMS m/z (M + 1, 330.1) 175

LCMS m/z (M + 1, 368.1) 176

LCMS m/z (M + 1, 320.1)

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

We claim:
 1. A method for treating cartilage damage, comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of a pharmaceutical combination comprising a compound of Formula1B and one or more therapeutic second agent;

or a pharmaceutically acceptable salt, or a stereoisomer thereof,wherein R¹ is phenyl or 5- or 6-membered heteroaryl, wherein the phenylor heteroaryl of R¹ is unsubstituted or substituted by 1 to 2substituents independently selected from halo, cyano, C₁₋₆alkyl,C₁₋₄haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b), 5- and 6-memberedheterocycloalkyl, phenyl, and 5- and 6-membered heteroaryl, wherein R¹³is C₁₋₆alkyl or amino; R^(14a) and R^(14b) are independently is selectedfrom hydrogen, C₁₋₆alkyl, —C(O)R¹⁵, and —C(O)OR¹⁵, wherein R¹⁵ isC₁₋₄alkyl; and the heterocycloalkyl, phenyl, or heteroaryl substituentof R¹ is unsubstituted or substituted by 1 to 2 substituentsindependently selected from halo, hydroxy, and C₁₋₆alkyl; R³ is phenylor 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl isunsubstituted or substituted by 1 to 2 substituents independentlyselected from halo, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, —C(O)R¹⁶, —C(O)OR¹⁶, 5- and 6-membered heterocycloalkyl,and phenyl, wherein R¹⁶ is C₁₋₆alkyl; and the heterocycloalkyl or phenylis unsubstituted or substituted by 1 to 2 substituents selected fromhalo and cyano; and R² and R⁴ are hydrogen.
 2. The method of claim 1,wherein the compound is of a formula selected from the formulae:


3. The method of claim 1, wherein R¹ is a 5 or 6 membered heteroaryl,unsubstituted or substituted by 1 to 2 substituents independentlyselected from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, and NHR^(14b), whereinR^(14b) is hydrogen or C₁₋₄alkyl.
 4. The method of claim 1, wherein R¹is selected from pyrazolyl, oxadiazolyl, pyridinyl, pyrimidinyl andpyrazinyl, wherein the pyrazolyl, pyridinyl, pyrimidinyl or pyrazinyl isunsubstituted or substituted by —NH₂, —NHC(O)OCH₃ or trifluoromethyl. 5.The method of claim 1, wherein R¹ is selected from

wherein “*” represents the point of attachment of R¹ to the bicycliccore ring.
 6. The method of claim 1, wherein R³ is phenyl substituted by1 to 2 substituents independently selected from halo, cyano, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, and phenyl, —C(O)R¹⁶,—C(O)OR¹⁶, wherein R¹⁶ is C₁₋₆alkyl, and the phenyl substituent of R³ isunsubstituted or further substituted by 1 to 2 substituentsindependently selected from halo and cyano.
 7. The method of claim 1,wherein R³ is selected from

wherein “*” represents the point of attachment of R³ to N.
 8. The methodof claim 1, wherein said one or more therapeutic agent is selected fromangiopoietin-like 3 protein (ANGPTL3), oral salmon calcitonin, SD-6010,vitamin D3, collagen hydrolyzate, FGF18, BMP7, rusalatide acetate,avocado soy unsaponifiables, a steroid, and a non-steroidalanti-inflammatory agent (NSAID) and hyaluronic acid.
 9. The method ofclaim 1, for treating articular cartilage damage.
 10. The method ofclaim 1, for treating cartilage damage in the joints.
 11. The method ofclaim 1, for treating cartilage damage in osteoarthritis.
 12. The methodof of claim 1, for treating cartilage damage in rheumatoid arthritis.13. The method of claim 1, wherein said compound of Formula 1B and saidone or more therapeutic second agent are administered simultaneously,sequentially or separately in a non-fixed combination.
 14. The method ofclaim 1, wherein said compound of Formula 1B is suitable forintra-articular delivery.
 15. The method of claim 14, wherein saidcompound of Formula 1B is suitable for intra-articular injection to theknee.
 16. The method of claim 1, wherein said Formula 1B is


17. The method of claim 1, wherein said Formula 1B is


18. The method of claim 1, wherein said Formula 1B


19. The method of claim 1, wherein said Formula 1B is


20. The method of claim 1, wherein said Formula 1B